WO2019215585A1 - Compositions comprising cd20 inhibitors and bisfluoroalkyl-1,4-benzodiazepinone compounds and methods of use thereof - Google Patents

Compositions comprising cd20 inhibitors and bisfluoroalkyl-1,4-benzodiazepinone compounds and methods of use thereof Download PDF

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WO2019215585A1
WO2019215585A1 PCT/IB2019/053696 IB2019053696W WO2019215585A1 WO 2019215585 A1 WO2019215585 A1 WO 2019215585A1 IB 2019053696 W IB2019053696 W IB 2019053696W WO 2019215585 A1 WO2019215585 A1 WO 2019215585A1
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composition
formula
subject
another embodiment
compound
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PCT/IB2019/053696
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French (fr)
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Roni Mamluk
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Ayala Pharmaceuticals Inc.
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Priority to US17/052,809 priority Critical patent/US20210379079A1/en
Priority to EP19800858.3A priority patent/EP3790553A4/en
Publication of WO2019215585A1 publication Critical patent/WO2019215585A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A61K31/551—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogen atoms, e.g. dilazep
    • A61K31/5513—1,4-Benzodiazepines, e.g. diazepam or clozapine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
    • A61K35/12—Materials from mammals; Compositions comprising non-specified tissues or cells; Compositions comprising non-embryonic stem cells; Genetically modified cells
    • A61K35/14—Blood; Artificial blood
    • A61K35/17—Lymphocytes; B-cells; T-cells; Natural killer cells; Interferon-activated or cytokine-activated lymphocytes
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
    • A61K39/39533—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals
    • A61K39/3955—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals against proteinaceous materials, e.g. enzymes, hormones, lymphokines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
    • A61K39/39533—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals
    • A61K39/39558—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals against tumor tissues, cells, antigens
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C07K16/2887—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against CD20

Definitions

  • compositions comprising bisfluoroalkyl-l ,4- benzodiazepinone compounds, including compounds of Formula (I) or prodrugs thereof;
  • an anti-CD20 agent in combination with an anti-CD20 agent, or other anti-CD20 therapy, and methods of use thereof for treating diseases and disorders such as cancer.
  • NOTCH activating mutations including, for example, NOTCH1 activating mutations
  • CLL Chronic Lymphocytic Leukemia
  • the present invention provides a composition comprising one or more compounds represented by the structure of Formula (I):
  • Ri is -CH 2 CF 3 or -CH 2 CH 2 CF 3
  • R 2 is -CH 2 CF 3 , -CH 2 CH 2 CF 3 , or -CH 2 CH 2 CH 2 CF 3 ;
  • R 3 is H, -CH 3 or Rx
  • R 4 is H or R y ;
  • R y is: -SCH 2 CH(NH 2 )C(0)0H, -SCH 2 CH(NH 2 )C(0)0H 3 ,
  • Ring A is phenyl or pyridinyl
  • each R a is independently F, Cl, -CN, -OCH 3 , Ci -3 alkyl, -CH 2 OH, -CF 3 ,
  • each R b is independently F, Cl, -CH 3 , -CH 2 OH, -CF 3 , cyclopropyl, and/or -OCFl 3 ;
  • y is zero, 1 or 2;
  • z is zero, 1 , or 2
  • the present invention also provides a method of increasing the efficacy of an anti-CD20 therapy in a subject, comprising the step of administering to said subject a first composition comprising one or more compounds represented by the structure of Formula (I):
  • Ri is -CH 2 CF 3 or -CH 2 CH 2 CF 3 ;
  • R 2 is -CH 2 CF 3 , -CH 2 CH 2 CF 3 , or -CH 2 CH 2 CH 2 CF 3 ;
  • R 3 is H, -CFl 3 or Rx
  • R 4 is Fl or R y ;
  • R y is: -SCH 2 CH(NH 2 )C(0)0H, -SCH 2 CH(NH 2 )C(0)0H 3 ,
  • Ring A is phenyl or pyridinyl
  • each R a is independently F, Cl, -CN, -OCH 3 , C 1-3 alkyl, -CH 2 OH, -CF 3 ,
  • each R b is independently F, Cl, -CH 3 , -CH 2 OH, -CF 3 , cyclopropyl, and/or -OCH 3 ;
  • y is zero, 1 or 2;
  • z is zero, 1 , or 2
  • the present invention also provides a method of treating a disease comprising a NOTCH1 activating mutation in a subject, the method comprising the step of administering to said subject a first composition comprising one or more compounds represented by the structure of Formula (I):
  • Ri is -CH 2 CF3 or -CH 2 CH 2 CF3;
  • R 2 is -CH2CF3, -CH2CH2CF3, or -CH2CH2CH2CF3;
  • R3 is H, -CH3 or Rx
  • R4 is Fl or R y ;
  • R y is: -SCH 2 CH(NH 2 )C(0)0H, -SCH 2 CH(NH 2 )C(0)0H 3 ,
  • Ring A is phenyl or pyridinyl
  • each R a is independently F, Cl, -CN, -OCH 3 , Ci -3 alkyl, -CH 2 OH, -CF 3 ,
  • each R b is independently F, Cl, -CH 3 , -CFl 2 OF[, -CF 3 , cyclopropyl, and/or -OCFl 3 ;
  • y is zero, 1 or 2;
  • z is zero, 1 , or 2
  • composition comprising an anti-CD20 monoclonal antibody.
  • the present invention also provides a method of treating Chronic Lymphocytic Leukemia (CLL) or a lymphoma associated with low CD20 expression levels in a subject, the method comprising the step of administering to said subject a first composition comprising one or more compounds represented by the structure of Formula (I):
  • Ri is -CH 2 CF 3 or -CH 2 CH 2 CF 3 ;
  • R 2 is -CH 2 CF 3 , -CH 2 CH 2 CF 3 , or -CH 2 CH 2 CH 2 CF 3 ;
  • R 3 is H, -CFl 3 or Rx
  • R 4 is Fl or R y ;
  • Rx is:
  • R y is: -SCH 2 CH(NH 2 )C(0)0H, -SCH 2 CH(NH 2 )C(0)0H 3 ,
  • Ring A is phenyl or pyridinyl
  • each R a is independently F, Cl, -CN, -OCH 3 , Ci -3 alkyl, -CH 2 OH, -CF 3 ,
  • each R b is independently F, Cl, -CH 3 , -CH 2 OH, -CF 3 , cyclopropyl, and/or -OCH 3 ;
  • y is zero, 1 or 2;
  • z is zero, 1 , or 2
  • composition comprising rituximab.
  • FIG. 1A Levels of CD20 in Lymphoma Cell Lines after treatment with g-secretase inhibitor (GSI), Compound 1.
  • GSI g-secretase inhibitor
  • Cells from five different lymphoma cell lines SP49 (MCL with Notch4 GOF); Toledo (DLBCL); RC (Double Hit DLBCL - MYC, BCL2); SUDHL-4 (DLBCL); and SUDHL-6 (DLBCL)
  • SP49 MCL with Notch4 GOF
  • RC Double Hit DLBCL - MYC, BCL2
  • SUDHL-4 DLBCL
  • SUDHL-6 DLBCL
  • Cell surface CD20 levels were observed by flow cytometry (FACS analysis).
  • Figure IB Levels of CD20 in Lymphoma Cell Lines after treatment with g-secretase inhibitor (GSI), Compound 22.
  • Cells from five different lymphoma cell lines SP49 (MCL with Notch4 GOF); Toledo (DLBCL); RC (Double Hit DLBCL - MYC, BCL2); SUDHL-4 (DLBCL); and SUDHL-6 (DLBCL)) were treated for 7 days with 0, lnM, lOnM, lOOnM, 500nM, lOOOnM, and 1 OOOOnM of the GSI compound 2.
  • Cell surface CD20 levels were observed by flow cytometry (FACS analysis).
  • FIG. 2A Levels of CD20 in Lymphoma Cell Lines after treatment with g-secretase inhibitor (GSI), Compound 1.
  • GSI g-secretase inhibitor
  • DLBCL lymphoma cell lines
  • MCL Rec-l
  • SP49 MCL
  • IhM IOhM
  • IOOhM 500nM
  • lOOOnM lOOOOnM
  • Cell surface CD20 levels were observed by flow cytometry (FACS analysis).
  • FIG. 2B Levels of CD20 in Lymphoma Cell Lines after treatment with g-secretase inhibitor (GSI), Compound 22.
  • GSI g-secretase inhibitor
  • FIG. 22B Cells from three different lymphoma cell lines (SUDHL-4 (DLBCL); Rec-l (MCL); and SP49 (MCL)) were treated for 7 days with 0, IhM, IOhM, lOOnM, 500nM, lOOOnM, and lOOOOnM of Compound 22.
  • Cell surface CD20 levels were observed by flow cytometry (FACS analysis).
  • FIGS 3A-3B Effect of g-secretase inhibitor (GSI) Compound 1 on viability in lymphoma cells.
  • GSI g-secretase inhibitor
  • compositions of the present invention or for use in the methods of the present invention comprise one or more gamma secretase inhibitors.
  • the gamma secretase inhibitor comprises a bisfluoroalkyl-l,4-benzodiazepinone compound.
  • compositions of the present invention or for use in the methods of the present invention comprise one or more NOTCH inhibitors.
  • the NOTCH inhibitor comprises a bisfluoroalkyl-l,4-benzodiazepinone compound.
  • compositions comprising compounds represented by the structure of Formula (I):
  • Ri is -CH2CF3 or -CH2CH2CF3;
  • R 2 is -CH 2 CF3, -CH 2 CH 2 CF3, or -CH 2 CH 2 CH 2 CF3 ;
  • R 3 is H, -CH 3 or Rx
  • R 4 is Fl or R y ;
  • R y is: -SCH 2 CH(NH 2 )C(0)0H, -SCH 2 CH(NH 2 )C(0)0H 3 ,
  • Ring A is phenyl or pyridinyl
  • each R a is independently F, Cl, -CN, -OCH 3 , C 1-3 alkyl, -CH 2 OH, -CF 3 ,
  • each Rb is independently F, Cl, -CH3, -CH2OH, -CF3, cyclopropyl, and/or -OCH3; y is zero, 1 or 2; and
  • z is zero, 1, or 2.
  • compositions comprising compounds represented by the structure of Formula (II):
  • R3 is H or -CH3; and y is zero or 1.
  • compositions comprising compounds of Formula (III):
  • Ri is -CH 2 CF3 or -CH 2 CH 2 CF3;
  • R 2 is -CH 2 CF3, -CH 2 CH 2 CF3, or -CH 2 CH 2 CH 2 CF3 ;
  • R 3 is Fl or -CH 3 ;
  • each R a is independently F, Cl, -CN, -OCH 3 , and/or -NHCH 2 CH 2 OCH 3 ;
  • y is zero, 1 , or 2.
  • R 2 is -CH 2 CF3 or -CH 2 CH 2 CF3.
  • Ri is -CH 2 CF3 or - CH 2 CH 2 CF3 and R 2 is -CH 2 CF3 or -CH 2 CH 2 CF3.
  • Ri is -CH 2 CH 2 CF3 and R 2 is -CH 2 CH 2 CF 3 .
  • y is zero or 1. In another embodiment, y is 1 or 2. In another embodiment, y is 1 or 2.
  • the compound of Formula (III) comprises: (2R,3S)— N-((3S)-l-methyl- 2-oxo-5-phenyl-2,3-dihydro-lH-l,4-benzodiazepin-3-yl)-2,3-bis(3,3,3-trifluoropropyl)succinamide (1)
  • the compound of Formula (III) comprises: (2R,3S)— N-((3S)-2-oxo- 5-phenyl-2,3-dihydro-lFl-l,4-benzodiazepin-3-yl)-2,3-bis(3,3,3-trifluoropropyl)succinamide (2)
  • the compound of Formula (III) comprises: (2R,3S)— N-((3S)-l- methyl-2-oxo-5-phenyl-2,3-dihydro-lFl-l,4-benzodiazepin-3-yl)-2-(2,2,2-trifluoroethyl)-3-(3,3,3- trifluoropropyl)succinamide (3);
  • the compound of Formula (III) comprises: (2R,3S)— N-((3S)-l- methyl-2-oxo-5-phenyl-2,3-dihydro-lH-l,4-benzodiazepin-3-yl)-3-(2,2,2-trifluoroethyl)-2-(3,3,3- trifluoropropyl)succinamide (4);
  • the compound of Formula (III) comprises: (2R,3S)— N-((3S)-l- ( 2 ]3 ⁇ 4)methyl-2-oxo-5-phenyl-2,3-dihydro-lF[-l,4-benzodiazepin-3-yl)-2,3-bis(3,3,3- trifluoropropyl)succinamide (5);
  • the compound of Formula (III) comprises a compound of Formula
  • the compound of Formula (III) comprises a compound of Formula (VII):
  • the compound of Formula (III) comprises: (2R,3S)— N-((3S)-2-oxo-
  • the compound of Formula (III) comprises: (2R,3S)— N-((3S)-8- methoxy-2-oxo-5-phenyl-2, 3-dihydro- 1H-1 ,4-benzodiazepin-3-yl)-3-(4,4,4-trifLuorobutyl)-2-(3,3,3- trifluoropropyl)succinamide (20) 20
  • the compound of Formula (III) comprises: (2R,3S)— N-((3S)-9-((2- methoxyethyl)amino)-2-oxo-5-phenyl-2,3-dihydro-lH-l,4-benzodiazepin-3-yl)-2,3-bis(3,3,3- triflu oropropyl)succinamide (21)
  • compositions comprising compounds represented by the structure of Formula (I):
  • Ri is -CH2CF3
  • R 2 is -CH2CH2CF3, or -CH2CH2CH2CF3;
  • R3 is H, -CH3 or Rx
  • R4 is H or R y ;
  • R y is: -SCH 2 CH(NH 2 )C(0)0H, -SCH 2 CH(NH 2 )C(0)0H 3 ,
  • Ring A is phenyl or pyridinyl
  • each R a is independently Cl, C1-3 alkyl, -CFhOFl, -CF3, cyclopropyl, -OCFh, and/or -O(cyclopropyl);
  • each R b is independently F, Cl, -CFh, -CFhOFl, -CF 3 , cyclopropyl, and/or -OCF13; y is zero, 1 or 2; and
  • z is 1 or 2.
  • Ring A is phenyl; and R3 is H.
  • R2 is -CH 2 CH 2 CF 3 ; and Ring A is phenyl.
  • R 2 is -CH 2 CH 2 CF 3 ; Ring A is phenyl; R a is Ci-3 alkyl or -CF1 2 0F1; each R b is independently F and/or Cl; and y is 1.
  • compositions comprising compounds represented by the structure of Formula (IV) :
  • compositions comprising compounds represented by the structure of Formula (V):
  • R3 is H or R x.
  • compositions comprising (2R,3S)-N- ((3S)-5-(3-fluorophenyl)-9-methyl-2-oxo-2,3-dihydro-lH-l,4-benzodiazepin-3-yl)-2,3-bis(3,3,3- trifluoropropyl)succinamide (22); (2R,3S)-N-((3S)-5-(3-chlorophenyl)-9-ethyl-2-oxo-2,3-dihydro- lH-l,4-benzodiazepin-3-yl)-2,3-bis(3,3,3-trifluoropropyl)succinamide (23); (2R,3S)-N-((3S)-5-(3- chlorophenyl)-9-isopropyl-2 -oxo-2, 3-dihydro-lH-l, 4-benzodiazepin-3-yl)-2,3-bis(
  • compositions comprising compounds represented by the structure of Formula (I):
  • Ri is -CH 2 CF3 or -CH 2 CH 2 CF3;
  • R 2 is -CH 2 CF3, -CH 2 CH 2 CF3, or -CH 2 CH 2 CH 2 CF3;
  • R 3 is H, -CH 3 or Rx
  • R4 is Fl or R y ;
  • R y is: -SCH 2 CH(NH 2 )C(0)0H, -SCH 2 CH(NH 2 )C(0)0H 3 ,
  • Ring A is phenyl or pyridinyl
  • each R a is independently F, Cl, -CN, -OCH 3 , C 1-3 alkyl, -CH 2 OH, -CF 3 ,
  • each Rb is independently F, Cl, -CH3, -CH 2 OH, -CF3, cyclopropyl, and/or -OCH3; y is zero, 1 or 2; and
  • z is zero, 1, or 2
  • Ring A is phenyl, z is zero, and y is 1 or 2 then at least one R a is Ci- 3 alkyl, -CH 2 OH, -CF 3 , cyclopropyl, or -O(cyclopropyl);
  • R 3 is R x then R 4 is H; and provided that if R4 is R y then R3 is H or -CH3.
  • a structure as described hereinabove comprises one or more of the following provisos: provided that if Ring A is phenyl, z is zero, and y is 1 or 2 then at least one R a is Ci- 3 alkyl, -CH 2 OH, -CF 3 , cyclopropyl, or -O(cyclopropyl); provided that if R 3 is R x then R 4 is H; and provided that if R 4 is R y then R 3 is H or -CH 3 .
  • compositions comprising compounds represented by the following structure:
  • the compounds as described herein comprise prodrugs of one or more of the compounds.
  • Ri is -CH 2 CH 2 CF3
  • R 2 is -CH 2 CH 2 CF3 or -CH 2 CH 2 CH 2 CF3;
  • R 3 is H, -CH 3 , or R x ;
  • R4 is Fl or R y ;
  • R y is: -SCH 2 CH(NH 2 )C(0)0H, -SCH 2 CH(NH 2 )C(0)0CH 3 ,
  • Ring A is phenyl or pyridinyl
  • each R a is independently Cl, Ci -3 alkyl, -CH 2 OH, -CF 3 , cyclopropyl, -OCH 3 ,
  • each R b is independently F, Cl, -CF1 3 , -CFl 2 OF[, -CF 3 , cyclopropyl, and/or -OCFl 3 ;
  • y is zero, 1 , or 2;
  • z is 1 or 2.
  • R 3 is H or -CH 3 ;
  • each R a is independently F, Cl, -CN, -OCH3 and/or -NHCH2CH2OCH3.
  • the present invention provides compositions comprising compounds as described herein formulated at a dose of 4 mg. In one embodiment, the present invention provides compositions comprising compounds as described herein formulated for intravenous administration.
  • compositions of the present invention or for use in the methods of the present invention comprise one or more cancer therapeutic agents in combination with one or more bisfluoroalkyl-l,4-benzodiazepinone compounds described hereinabove.
  • the cancer therapeutic agent comprises an anti-CD20 agent.
  • the present invention provides a composition comprising one or more compounds represented by the structure of Formula (I) and an anti-CD20 agent as described herein in combination with an immunotherapeutic.
  • the immunotherapeutic comprises a monoclonal antibody.
  • the monoclonal antibody comprises an anti-CD20 antibody.
  • Anti- CD20 antibodies can bind to CD20 and mediate antibody dependent cell death and complement cell death, by natural killer (NK) cells, thus eliminating malignant B-cells.
  • the anti- CD20 antibody comprises rituximab.
  • the anti-CD20 antibody comprises a rituximab biosimilar, or any next generation anti-CD20.
  • the anti-CD20 antibody comprises any other anti-CD20 antibody suitable for use in accordance with the compositions and methods described herein, including, without limitation, ocrelizumab, Ocaratuzumab (including AME-D, AME-l33v, LY2469298) veltuzumab (including subcutaneous, ha20, IMMU-106, intravenous), obinutuzumab (including GA101 ; Gazyva, Gazyvaro, RO5072759, RG7159), ofatumumab (including Arzerra OMB157, humax-cd20, 2F2), tositumomab (including Bexxar), ibritumomab (including Zevalin, ibritumamab tiuxetan (IDEC-Y2B8)), Prol 31921 (RhuMAb; vl l4), TRU-015, Ublituximab (including LFB-R603, EMAB-6
  • the present invention provides methods that include administering a composition comprising one or more compounds represented by the structure of Formula (I) as described herein in combination with an anti-CD20 therapy.
  • the anti-CD20 therapy comprises any other anti-CD20 therapy suitable for use in accordance with the compositions and methods described herein, including, without limitation, CAR-T therapy, bispecific antibodies, T cell engagers, antibody drug conjugates, or a combination thereof.
  • an anti-CD20 agent as described herein comprises a CD20 modulatory compound or reagent.
  • the CD20 modulatory compound or reagent comprises Bryostatin-1, Interleukin-4, GMCSF, Tumor necrosis factor-a, one or more Statins, Interferon-a, L- 744,832, Bortezomib, 5-azacytidine, Trichostatin-A, Valproic acid (VPA) or Romidepsin, or a combination thereof.
  • radiation treatment modulates CD20.
  • the anti-CD20 agent comprises an anti-CD20 antibody.
  • the anti-CD20 antibody comprises an anti-CD20 monoclonal antibody.
  • compositions of the present invention or for use in the methods of the present invention comprise one or more compounds represented by the structure of Formula (I) as described herein in combination with rituximab.
  • compositions of the present invention or for use in the methods of the present invention comprise one or more additional cancer therapeutic agents in combination with one or more bisfluoroalkyl-l ,4-benzodiazepinone compounds and one or more anti-CD20 agent.
  • chemotherapeutic agents and/or other treatments are often advantageous.
  • An additional agent may have the same or different mechanism of action than the primary therapeutic agents.
  • drug combinations may be employed wherein the two or more drugs being administered act in different manners or in different phases of the cell cycle, and/or where the two or more drugs have nonoverlapping toxicities or side effects, and/or where the drugs being combined each has a demonstrated efficacy in treating the particular disease state manifested by the patient.
  • a method for treating cancer comprising administering to a mammal in need thereof a composition as described herein and administering one or more additional anti-cancer agents.
  • the phrase“additional anti-cancer agent” refers to a drug selected from any one or more of the following: alkylating agents (including nitrogen mustards, methanesulphonate, busulphan, alkyl sulfonates, nitrosoureas, ethylenimine derivatives, and triazenes, or a combination thereof); anti-angiogenics (including matrix metalloproteinase inhibitors); antimetabolites (including adenosine deaminase inhibitors, folic acid antagonists, purine analogues, and pyrimidine analogues); antibiotics or antibodies (including monoclonal antibodies, CTLA-4 antibodies, anthracyclines); aromata.se inhibitors; cell-cycle response modifiers; enzymes; farnesyl-protein transferase inhibitors; hormonal and antihormonal agents and steroids (including synthetic analogs, glucocorticoids, estrogens/anti-estrogens [e.g.,
  • the present invention provides a composition comprising one or more compounds represented by the structure of Formula (I) and an anti-CD20 agent as described herein in combination with an inhibitor of mammalian target of rapamycin (mTOR).
  • mTOR mammalian target of rapamycin
  • the mTOR inhibitor comprises Everolimus.
  • the mTOR inhibitor comprises sirolimus (rapamycin).
  • the mTOR inhibitor comprises temsirolimus.
  • the mTOR inhibitor comprises a dual mammalian target of rapamycin/phosphoinositide 3-kinase inhibitor, which in one embodiment, comprises NVP-BEZ235 (dactolisib), GSK2126458, XL765, or a combination thereof.
  • the mTOR inhibitor comprises a second generation mTOR inhibitor, which, in one embodiment, comprises AZD8055, INK128/MLN0128, OSI027, or a combination thereof.
  • the mTOR inhibitor comprises a third generation mTOR inhibitor, which, in one embodiment, comprises RapaLinks.
  • the present invention provides a composition comprising one or more compounds represented by the structure of Formula (I) and an anti-CD20 agent as described herein in combination with an mTOR inhibitor and a chemotherapeutic drug.
  • the mTOR inhibitor comprises everolimus.
  • the chemotherapeutic drug comprises cisplatin.
  • the present invention provides a composition comprising one or more compounds represented by the structure of Formula (I) and an anti-CD20 agent as described herein in combination with bisphosphonates.
  • the present invention provides a composition comprising one or more compounds represented by the structure of Formula (I) and an anti-CD20 agent as described herein in combination with cancer growth blockers.
  • the present invention provides a composition comprising one or more compounds represented by the structure of Formula (I) and an anti-CD20 agent as described herein in combination with proteasome inhibitors.
  • the present invention provides a composition comprising one or more compounds represented by the structure of Formula (I) and an anti-CD20 agent as described herein in combination with one or more interferons.
  • the present invention provides a composition comprising one or more compounds represented by the structure of Formula (I) and an anti-CD20 agent as described herein in combination with one or more interleukins.
  • the present invention provides a composition comprising one or more compounds represented by the structure of Formula (I) and an anti-CD20 agent as described herein in combination with an alkylating drug.
  • the alkylating drug comprises Procarbazine (Matulane), dacarbazine (DTIC), Altretamine (Flexalen), or a combination thereof.
  • the present invention provides a composition comprising one or more compounds represented by the structure of Formula (I) and an anti-CD20 agent as described herein in combination with an antimetabolite.
  • the antimetabolite comprises an antifolic acid compound (Methotrexate), an amino acid antagonists (Azaserine), or a combination thereof.
  • the present invention provides a composition comprising one or more compounds represented by the structure of Formula (I) and an anti-CD20 agent as described herein in combination with a purine antagonist.
  • the purine antagonist comprises Mercaptopurine (6-MP), Thioguanine (6-TG), Fludarabine Phosphate, Cladribine (Leustatin), Pentostatin (Nipent), or a combination thereof.
  • the present invention provides a composition comprising one or more compounds represented by the structure of Formula (I) and an anti-CD20 agent as described herein in combination with a pyrimidine antagonist.
  • the pyrimidine antagonist comprises Fluorouracil (5-FU), Cytarabine (ARA-C), Azacitidine, or a combination thereof.
  • the present invention provides a composition comprising one or more compounds represented by the structure of Formula (I) and an anti-CD20 agent as described herein in combination with a plant alkaloid.
  • the pyrimidine antagonist comprises Vinblastine (Velban), Vincristine (Oncovin), Etoposide (VP-16, VePe-sid), Teniposide (Vumon), Topotecan (Hycamtin), Irinotecan (Camptosar), Paclitaxel (Taxol), Docetaxel (Taxotere), or a combination thereof.
  • the present invention provides a composition comprising one or more compounds represented by the structure of Formula (I) and an anti-CD20 agent as described herein in combination with FOLFIRI, wherein in one embodiment FOLFIRI comprises folinic acid (leucovorin), fluorouracil (5-FU) and irinotecan (Camptosar).
  • FOLFIRI comprises folinic acid (leucovorin), fluorouracil (5-FU) and irinotecan (Camptosar).
  • the present invention provides a composition comprising one or more compounds represented by the structure of Formula (I) and an anti-CD20 agent as described herein in combination with folinic acid (leucovorin), fluorouracil (5-FU), irinotecan (Camptosar), or a combination thereof.
  • the present invention provides a composition comprising one or more compounds represented by the structure of Formula (I) and an anti-CD20 agent as described herein in combination with an antibiotic.
  • the antibiotic comprises Anthracyclines, Doxorubicin (Adriamycin, Rubex, Doxil), Daunorubicin (DaunoXome), Dactinomycin (Cosmegen), Idarubincin (Idamycin), Plicamycin (Mithramycin), Mitomycin (Mutamycin), Bleomycin (Blenoxane), or a combination thereof.
  • the present invention provides a composition comprising one or more compounds represented by the structure of Formula (I) and an anti-CD20 agent as described herein in combination with an immunotherapeutic.
  • the immunotherapeutic comprises a monoclonal antibody.
  • the monoclonal antibody comprises an anti-PD-1 antibody, which in one embodiment comprises nivolumab.
  • the monoclonal antibody comprises alemtuzumab (Campath®), trastuzumab (Herceptin®), Bevacizumab (Avastin®), Cetuximab (Erbitux®), or a combination thereof.
  • the monocolonal antibody comprises a radiolabeled antibody, which, in one embodiment, comprises britumomab, tiuxetan (Zevalin®), or a combination thereof.
  • the monocolonal antibody comprises a chemolabeied antibody, which in one embodiment comprises Brentuximab vedotin (Adcetris ® ), Ado-trastuzumab emtansine (Kadcyla ® , also called TDM-1), denileukin diftitox (Ontak ® ), or a combination thereof
  • the monocolonal antibody comprises a bispecific antibody, which in one embodiment, comprises blinatumomab (Blincyto).
  • the present invention provides a composition comprising one or more compounds represented by the structure of Formula (I) and an anti-CD20 agent as described herein in combination with a hormonal agent.
  • the hormonal agent comprises Tamoxifen (Nolvadex), Flutamide (Eulexin), Gonadotropin-Releasing Flormone Agonists, (Leuprolide and Goserelin (Zoladex)), Aromatase Inhibitors, Aminoglutethimide, Anastrozole (Arimidex), or a combination thereof.
  • the present invention provides a composition comprising one or more compounds represented by the structure of Formula (I) and an anti-CD20 agent as described herein in combination with Amsacrine, Hydroxyurea (Hydrea), Asparaginase (El-spar), Mitoxantrone (Novantrone), Mitotane, Retinoic Acid Derivatives, Bone Marrow Growth Factors, Amifostine, or a combination thereof.
  • the present invention provides a composition comprising one or more compounds represented by the structure of Formula (I) and an anti-CD20 agent as described herein in combination with an agent that inhibits one or more cancer stem cell pathways.
  • an agent comprises an inhibitor of Hedgehog, WNT, BMP, or a combination thereof.
  • the present invention provides a composition comprising one or more compounds represented by the structure of Formula (I) and an anti-CD20 agent as described herein in combination with any one or more of the following: Revlimid, Avastin, Herceptin, Rituxan, Opdivo, Gleevec, Imbruvica, Velcade, Zytiga, Xtandi, Alimta, Gadasil, Ibrance, Perjeta, Tasigna, Xgeva, Afinitor, Jakafi, Tarceva, Keytruda, Sutent, Yervoy, Nexavar, Zoladex, Erbitux, Dazalex, Xeloda, Gazyva, Venclexta, and Tecentriq.
  • the present invention provides a composition comprising one or more compounds represented by the structure of Formula (I) and an anti-CD20 agent as described herein in combination with any one or more of the following: abemaciclib, epacadostat, apalutamide, Carfilzomib, Crizotinib (PF-02341066), GDC-0449 (vismodegib), OncoVex, PLX4032 (RG7204), Ponatinib, SGN-35 (brentuximab vedotin), Tivozanib (AV-951), T-DM1 (Trastuzumab-DMl), and XL184 (cabozantinib).
  • compositions of the present invention may be administered in combination with other anti-cancer treatments useful in the treatment of cancer or other proliferative diseases.
  • the invention herein further comprises use of the compositions of the present invention in preparing medicaments for the treatment of cancer, and/or it comprises the packaging of the compositions of the present invention together with instructions that the compositions be used in combination with other anti-cancer or cytotoxic agents and treatments for the treatment of cancer.
  • the compounds of the present invention can be formulated or co-administered with other therapeutic agents that are selected for their particular usefulness in addressing side effects associated with the aforementioned conditions.
  • compounds of the invention may be formulated with agents to prevent nausea, hypersensitivity and gastric irritation, such as antiemetics, and Hi and ih antihistaminics.
  • compositions comprising a compound of Formula (I) or prodrug thereof; one or more additional agents selected from a kinase inhibitory agent (small molecule, polypeptide, and antibody), an immunosuppressant, an anti-cancer agent, an anti viral agent, anti-inflammatory agent, antifungal agent, antibiotic, or an anti-vascular hyperproliferation compound; and any pharmaceutically acceptable carrier, adjuvant or vehicle.
  • a kinase inhibitory agent small molecule, polypeptide, and antibody
  • an immunosuppressant an anti-cancer agent
  • an anti viral agent anti-inflammatory agent
  • antifungal agent antifungal agent
  • antibiotic antibiotic
  • anti-vascular hyperproliferation compound any pharmaceutically acceptable carrier, adjuvant or vehicle.
  • therapeutic agents when employed in combination with the compounds of the present invention, may be used, for example, in those amounts indicated in the Physicians' Desk Reference (PDR) or as otherwise determined by one of ordinary skill in the art.
  • PDR Physicians' Desk Reference
  • such other therapeutic agent(s) may be administered prior to, simultaneously with, or following the administration of the inventive compounds.
  • compositions comprising the compound of Formula (I) and one or more non-toxic, pharmaceutically- acceptable carriers and/or diluents and/or adjuvants (collectively referred to herein as“carrier” materials) and, if desired, other active ingredients.
  • the compounds of Formula (I) may be administered by any suitable route, preferably in the form of a pharmaceutical composition adapted to such a route, and in a dose effective for the treatment intended.
  • the compounds and compositions of the present invention may, for example, be administered in dosage unit formulations containing conventional pharmaceutically or food grade acceptable carriers, adjuvants, and vehicles.
  • the pharmaceutical carrier may contain a mixture of mannitol or lactose and microcrystalline cellulose.
  • the mixture may contain additional components such as a lubricating agent, e.g., magnesium stearate and a disintegrating agent such as crospovidone.
  • the carrier mixture may be filled into a gelatin capsule or compressed as a tablet.
  • the pharmaceutical composition may be administered as an oral dosage form or an infusion, for example.
  • the pharmaceutical composition may be in the form of, for example, a tablet, capsule, liquid capsule, suspension, or liquid.
  • the pharmaceutical composition is preferably made in the form of a dosage unit containing a particular amount of the active ingredient.
  • the pharmaceutical composition may be provided as a tablet or capsule comprising an amount of active ingredient in the range of from about 0.3 to 2000 mg, preferably from about 0.3 to 500 mg, and more preferably from about 5 to 150 mg.
  • a suitable daily dose for a human or other mammal may vary widely depending on the condition of the patient and other factors, but, can be determined using routine methods.
  • dosing can be modified to achieve desired results by utilizing a modified appropriate dosing schedule, such as, for example, twice a week dosing or other suitable schedule.
  • a modified appropriate dosing schedule such as, for example, twice a week dosing or other suitable schedule.
  • Any pharmaceutical composition contemplated herein can, for example, be delivered orally via any acceptable and suitable oral preparations.
  • exemplary oral preparations include, but are not limited to, for example, tablets, troches, lozenges, pills, aqueous and oily suspensions, dispersible powders, pellets or granules, emulsions, hard and soft capsules, liquid capsules, syrups, and elixirs.
  • Pharmaceutical compositions intended for oral administration can be prepared according to any methods known in the art for manufacturing pharmaceutical compositions intended for oral administration.
  • Tablet and other oral preparations also can include, without limitation, buccal, chewable, effervescent, modified release, orally disintegrating, sublingual, for oral solution, for oral suspension, triturates, or any other forms suitable for use in accordance with the compositions and methods described herein.
  • a pharmaceutical composition in accordance with the invention can contain at least one agent selected from sweetening agents, flavoring agents, coloring agents, demulcents, antioxidants, and preserving agents.
  • a tablet can, for example, be prepared by admixing at least one compound of Formula (I) with at least one non-toxic pharmaceutically acceptable excipient suitable for the manufacture of tablets.
  • excipients include, but are not limited to, for example, inert diluents, such as, for example, calcium carbonate, sodium carbonate, lactose, calcium phosphate, and sodium phosphate; granulating and disintegrating agents, such as, for example, microcrystalline cellulose, sodium croscarmellose, com starch, and alginic acid; binding agents, such as, for example, starch, gelatin, polyvinyl-pyrrolidone, and acacia; and lubricating agents, such as, for example, magnesium stearate, stearic acid, and talc.
  • inert diluents such as, for example, calcium carbonate, sodium carbonate, lactose, calcium phosphate, and sodium phosphate
  • granulating and disintegrating agents such as
  • a tablet can either be uncoated, or coated or encapsulated by known techniques to either mask the bad taste of an unpleasant tasting drug, or delay disintegration and absorption of the active ingredient in the gastrointestinal tract thereby sustaining the effects of the active ingredient for a longer period.
  • Exemplary water soluble taste masking materials include, but are not limited to, hydroxypropyl-methylcellulose and hydroxypropyl-cellulose.
  • Exemplary time delay materials include, but are not limited to, ethyl cellulose, poly (meth) acrylate and cellulose acetate butyrate.
  • a formulation can be prepared to include only drug substance.
  • Hard gelatin capsules can, for example, be prepared by mixing at least one compound of Formula (I) with at least one inert solid diluent, such as, for example, calcium carbonate; calcium phosphate; and kaolin. Alternatively, if desired, the capsule can be prepared to include only drug substance.
  • at least one compound of Formula (I) with at least one inert solid diluent, such as, for example, calcium carbonate; calcium phosphate; and kaolin.
  • the capsule can be prepared to include only drug substance.
  • Soft gelatin capsules can, for example, be prepared by mixing at least one compound of Formula (I) with at least one water soluble carrier, such as, for example, polyethylene glycol; and at least one oil medium, such as, for example, peanut oil, liquid paraffin, and olive oil.
  • at least one water soluble carrier such as, for example, polyethylene glycol
  • at least one oil medium such as, for example, peanut oil, liquid paraffin, and olive oil.
  • An aqueous suspension can be prepared, for example, by admixing at least one compound of Formula (I) with at least one excipient suitable for the manufacture of an aqueous suspension.
  • excipients suitable for the manufacture of an aqueous suspension include, but are not limited to, for example, suspending agents, such as, for example, sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethyl-cellulose, sodium alginate, alginic acid, polyvinyl pyrrolidone, gum tragacanth, and gum acacia; dispersing or wetting agents, such as, for example, a naturally-occurring phosphatide, e.g., lecithin; condensation products of alkylene oxide with fatty acids, such as, for example, polyoxyethylene stearate; condensation products of ethylene oxide with long chain aliphatic alcohols, such as, for example heptadecaethylene-oxycetanol; condensation products of ethylene oxide with partial esters derived from a suspending agents
  • An aqueous suspension can also contain at least one preservative, such as, for example, ethyl and n-propyl p-hydroxybenzoate; at least one coloring agent; at least one flavoring agent; and/or at least one sweetening agent, including but not limited to, for example, sucrose, saccharin, and aspartame.
  • Oily suspensions can, for example, be prepared by suspending at least one compound of Formula (I) in either a vegetable oil, such as, for example, arachis oil; olive oil; sesame oil; and coconut oil; or in mineral oil, such as, for example, liquid paraffin.
  • An oily suspension can also contain at least one thickening agent, such as, for example, beeswax; hard paraffin; and cetyl alcohol.
  • at least one of the sweetening agents already described hereinabove, and/or at least one flavoring agent can be added to the oily suspension.
  • An oily suspension can further contain at least one preservative, including, but not limited to, for example, an antioxidant, such as, for example, butylated hydroxyanisol, and alpha-tocopherol.
  • Dispersible powders and granules can, for example, be prepared by admixing at least one compound of Formula (I) with at least one dispersing and/or wetting agent; at least one suspending agent; and/or at least one preservative.
  • Suitable dispersing agents, wetting agents, and suspending agents are as already described above.
  • Exemplary preservatives include, but are not limited to, for example, anti-oxidants, e.g., ascorbic acid.
  • dispersible powders and granules can also contain at least one excipient, including, but not limited to, for example, sweetening agents; flavoring agents; and coloring agents.
  • An emulsion of at least one compound of Formula (I) can, for example, be prepared as an oil- in-water emulsion.
  • the oily phase of the emulsions comprising compounds of Formula (I) may be constituted from known ingredients in a known manner.
  • the oil phase can be provided by, but is not limited to, for example, a vegetable oil, such as, for example, olive oil and arachis oil; a mineral oil, such as, for example, liquid paraffin; and mixtures thereof. While the phase may comprise merely an emulsifier, it may comprise a mixture of at least one emulsifier with a fat or an oil or with both a fat and an oil.
  • Suitable emulsifying agents include, but are not limited to, for example, naturally- occurring phosphatides, e.g., soy bean lecithin; esters or partial esters derived from fatty acids and hexitol anhydrides, such as, for example, sorbitan monooleate; and condensation products of partial esters with ethylene oxide, such as, for example, polyoxyethylene sorbitan monooleate.
  • a hydrophilic emulsifier is included together with a lipophilic emulsifier which acts as a stabilizer. It is also preferred to include both an oil and a fat.
  • emulsifier(s) with or without stabilizer(s) make-up the so-called emulsifying wax
  • the wax together with the oil and fat make up the so- called emulsifying ointment base which forms the oily dispersed phase of the cream formulations.
  • An emulsion can also contain a sweetening agent, a flavoring agent, a preservative, and/or an antioxidant.
  • Emulsifiers and emulsion stabilizers suitable for use in the formulation of the present invention include Tween 60, Span 80, cetostearyl alcohol, myristyl alcohol, glyceryl monostearate, sodium lauryl sulfate, glyceryl distearate alone or with a wax, or other materials well known in the art.
  • the compounds of Formula (I) can be formulated as a nanoparticle, lipid nanoparticle, microparticle or liposome.
  • the compounds of Formula (I) can, for example, also be delivered intravenously, subcutaneously, and/or intramuscularly via any pharmaceutically acceptable and suitable injectable form.
  • injectable forms include, but are not limited to, for example, sterile aqueous solutions comprising acceptable vehicles and solvents, such as, for example, water, Ringer's solution, and isotonic sodium chloride solution; sterile oil-in-water microemulsions; and aqueous or oleaginous suspensions.
  • the composition may be provided for intravenous administration comprising an amount of active ingredient in the range of from about 0.2 to 150 mg.
  • the active ingredient is present in the range of from about 0.3 to 10 mg.
  • the active ingredient is present in the range of from about 4 to 8.4 mg.
  • the active ingredient is administered at a dose of about 4 mg.
  • the active ingredient is administered at a dose of about 6 mg.
  • the active ingredient is administered at a dose of about 8.4 mg.
  • the active ingredient is administered at a dose of about 0.3 mg. In another embodiment, the active ingredient is administered at a dose of about 0.6 mg. In another embodiment, the active ingredient is administered at a dose of about 1.2 mg. In another embodiment, the active ingredient is administered at a dose of about 2.4 mg.
  • Formulations for parenteral administration may be in the form of aqueous or non-aqueous isotonic sterile injection solutions or suspensions. These solutions and suspensions may be prepared from sterile powders or granules using one or more of the carriers or diluents mentioned for use in the formulations for oral administration or by using other suitable dispersing or wetting agents and suspending agents.
  • the compounds may be dissolved in any suitable solvent, including, without limitation, water, polyethylene glycol, propylene glycol, ethanol, com oil, cottonseed oil, peanut oil, sesame oil, benzyl alcohol, sodium chloride, tragacanth gum, and/or various buffers.
  • the active ingredient may also be administered by injection as a composition with suitable carriers including saline, dextrose, or water, or with cyclodextrin (i.e., CAPTISOF®), cosolvent solubilization (i.e., propylene glycol) or micellar solubilization (i.e., Tween 80).
  • suitable carriers including saline, dextrose, or water, or with cyclodextrin (i.e., CAPTISOF®), cosolvent solubilization (i.e., propylene glycol) or micellar solubilization (i.e., Tween 80).
  • the sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, for example as a solution in 1 ,3-butanediol.
  • a non-toxic parenterally acceptable diluent or solvent for example as a solution in 1 ,3-butanediol.
  • acceptable parenterally acceptable diluents and solvents that may be employed are water, Ringer's solution, and isotonic sodium chloride solution.
  • sterile, fixed oils are conventionally employed as a solvent or suspending medium.
  • any bland fixed oil may be employed, including synthetic mono- or diglycerides.
  • fatty acids such as oleic acid find use in the preparation of injectables.
  • a sterile injectable oil-in-water nano or microemulsion can, for example, be prepared by 1) dissolving at least one compound of Formula (I) in an oily phase, such as, for example, a mixture of soybean oil and lecithin; 2) combining the Formula (I) containing oil phase with a water and glycerol mixture; and 3) processing the combination to form a microemulsion.
  • an oily phase such as, for example, a mixture of soybean oil and lecithin
  • combining the Formula (I) containing oil phase with a water and glycerol mixture and 3) processing the combination to form a microemulsion.
  • a sterile aqueous or oleaginous suspension can be prepared in accordance with methods already known in the art.
  • a sterile aqueous solution or suspension can be prepared with a non-toxic parenter ally- acceptable diluent or solvent, such as, for example, 1,3-butane diol; and a sterile oleaginous suspension can be prepared with a sterile non-toxic acceptable solvent or suspending medium, such as, for example, sterile fixed oils, e.g., synthetic mono- or diglycerides; and fatty acids, such as, for example, oleic acid.
  • Pharmaceutically acceptable carriers, adjuvants, and vehicles that may be used in the pharmaceutical compositions of this invention include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, self-emulsifying drug delivery systems (SEDDS) such as d- alpha-tocopherol polyethyleneglycol 1000 succinate, surfactants used in pharmaceutical dosage forms such as Tweens, polyethoxylated castor oil such as CREMOPFlOR® surfactant (BASF), or other similar polymeric delivery matrices, serum proteins, such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrroli
  • Cyclodextrins such as alpha-, beta-, and gamma- cyclodextrin, or chemically modified derivatives such as hydroxyalkyl-cyclodextrins, including 2- and 3-hydroxypropyl-cyclodextrins, or other solubilized derivatives may also be advantageously used to enhance delivery of compounds of the formulae described herein.
  • the pharmaceutically active compounds of this invention can be processed in accordance with conventional methods of pharmacy to produce medicinal agents for administration to patients, including humans and other mammals.
  • the pharmaceutical compositions may be subjected to conventional pharmaceutical operations such as sterilization and/or may contain conventional adjuvants, such as preservatives, stabilizers, wetting agents, emulsifiers, buffers etc. Tablets and pills can additionally be prepared with enteric coatings.
  • Such compositions may also comprise adjuvants, such as wetting, sweetening, flavoring, and perfuming agents.
  • the amounts of compounds that are administered and the dosage regimen for treating a disease condition with the compounds and/or compositions of this invention depends on a variety of factors, including the age, weight, gender, the medical condition of the subject, the type of disease, the severity of the disease, the route and frequency of administration, and the particular compound employed. Thus, the dosage regimen may vary widely, but can be determined routinely using standard methods.
  • the daily dose can be administered in one to four doses per day.
  • the compound is administered to the subject once a week. In another embodiment, the compound is administered to the subject once every two weeks.
  • the active compounds of this invention are ordinarily combined with one or more adjuvants appropriate to the indicated route of administration.
  • the compounds may be admixed with lactose, sucrose, starch powder, cellulose esters of alkanoic acids, cellulose alkyl esters, talc, stearic acid, magnesium stearate, magnesium oxide, sodium and calcium salts of phosphoric and sulfuric acids, gelatin, acacia gum, sodium alginate, polyvinylpyrrolidone, and/or polyvinyl alcohol, and then tableted or encapsulated for convenient administration.
  • Such capsules or tablets may contain a controlled-release formulation as may be provided in a dispersion of active compound in hydroxypropylmethyl cellulose.
  • compositions of this invention comprise at least one compound of Formula (I) and/or at least one salt thereof, and optionally an additional agent selected from any pharmaceutically acceptable carrier, adjuvant, and vehicle.
  • Alternate compositions of this invention comprise a compound of the Formula (I) described herein, or a prodmg thereof, and a pharmaceutically acceptable carrier, adjuvant, or vehicle.
  • the compound in accordance with Formula (I) can be administered by any means suitable for the condition to be treated, which can depend on the need for site-specific treatment or quantity of Formula (I) compound to be delivered.
  • the compounds and compositions of the present invention may, for example, be administered orally, mucosally, or parentally including intravascularly, intraperitoneally, subcutaneously, intramuscularly, and intrasternally. In another embodiment, the compounds and compositions of the present invention are administered intravenously.
  • the present invention provides the use of the described compounds or compositions for treating, suppressing or inhibiting a disease in a subject and the use of the described compounds or compositions for increasing the efficacy of an anti-CD20 therapy in a subject.
  • the anti-CD20 therapy comprises an anti-CD20 agent.
  • the anti- CD20 therapy comprises CAR-T therapy.
  • the anti-CD20 therapy comprises a bispecific antibody.
  • the anti-CD20 therapy comprises a T cell engager.
  • the anti-CD20 therapy comprises an antibody drug conjugate.
  • the present invention provides a method of treating a disease comprising a NOTCH activating mutation in a subject comprising the step of administering to said subject a first composition comprising one or more compounds represented by the structure of Formula (I):
  • Ri is— CH 2 CF 3 or— CH 2 CH 2 CF 3 ;
  • R 2 is— CH2CF3,— CH2CH2CF3, or— CH2CH2CH2CF3;
  • R 3 is H or— C3 ⁇ 4;
  • each R a is independently F, Cl,— CN,— OCH3, and/or— NHCH 2 CH 2 OCH3; and z is zero, 1, or 2
  • composition comprising an anti-CD20 agent.
  • the compound of Formula I comprises:
  • the compound of Formula I comprises:
  • the compound of Formula I comprises:
  • the subject has activated Notch and low CD20.
  • the diseased cells in the subject comprise activated Notch and low CD20.
  • the disease in the subject is refractory to anti-CD20 treatment.
  • the subject has not previously been treated with anti-CD20, alone or in combination with other treatments.
  • a method for increasing the efficacy of an anti-CD20 agent or other anti-CD20 therapy, comprising administering to a subject a compound of Formula (I) and said anti-CD20 agent or other therapy.
  • a method is provided for increasing the efficacy of an anti-CD20 monoclonal antibody comprising administering to a subject a compound of Formula (I) and an anti-CD20 monoclonal antibody, which in one embodiment comprises rituximab.
  • a method for increasing the efficacy of an anti-CD20 monoclonal antibody comprising administering to a subject a compound of Formula (I) and an anti- CD20 monoclonal antibody, which in one embodiment comprises Ofatumumab.
  • a method for increasing the efficacy of an anti-CD20 monoclonal antibody comprising administering to a subject a compound of Formula (I) and an anti-CD20 monoclonal antibody, which in one embodiment comprises Obinutuzumab.
  • increasing the efficacy of the anti-CD20 monoclonal antibody comprises decreasing resistance to the anti-CD20 monoclonal antibody.
  • increasing the efficacy of the anti-CD20 monoclonal antibody comprises prolonging survival in the subject.
  • increasing the efficacy comprises achieving complete remission in the subject.
  • increasing the efficacy comprises achieving partial remission in the subject.
  • increasing the efficacy comprises achieving stable disease in the subject.
  • achieving stable disease in the subject comprises decreasing the level of Minimal Residual Disease (MRD) in the subject.
  • achieving stable disease in the subject comprises decreasing the progression of disease and/or rate of MRD. Any other measure of increasing efficacy, or combination of measures, known in the art is also within the scope of the invention as described herein.
  • a method for treating a disease comprising a NOTCH activating mutation comprising administering to a subject a compound of Formula (I) and an anti- CD20 agent, which in one embodiment, comprises an anti-CD20 monoclonal antibody, which in one embodiment comprises rituximab, ofatumumab, obinutuzumab, or a combination thereof.
  • the NOTCH activating mutation is any NOTCH activating mutation.
  • the NOTCH activating mutation is a NOTCH1 activating mutation.
  • the NOTCH activating mutation is a NOTCH2 activating mutation.
  • the NOTCH activating mutation is a NOTCH3 activating mutation.
  • the NOTCH activating mutation is a NOTCH4 activating mutation.
  • benzodiazepinone compounds as described herein increase expression of CD20. In another embodiment, benzodiazepinone compounds as described herein are effective via a different mechanism of action.
  • the disease comprises a lymphoid neoplasm.
  • the lymphoid neoplasm comprises a CD20 leukemia.
  • the lymphoid neoplasm comprises Chronic Lymphocytic Leukemia (CLL).
  • CLL Chronic Lymphocytic Leukemia
  • the lymphoid neoplasm comprises Small Lymphocytic Leukemia (SLL), mantle cell lymphoma (MCL), marginal zone lymphoma, diffuse large B-cell lymphoma (DLBCL), splenic diffuse red pulp small B-cell lymphoma, follicular lymphoma, or a combination thereof.
  • the lymphoid neoplasm comprises pediatric T-cell acute lymphoblastic leukemia/lymphoma (T-ALL), adult T- ALL, pediatric early T-cell precursor acute lymphoblastic leukemia (ETP-ALL), adult ETP-ALL, Adult T-cell leukemia/lymphoma, or a combination thereof.
  • the disease is associated with low CD20 expression levels in the subject.
  • the disease comprises Richter Syndrome.
  • the disease associated with low CD20 expression levels comprises Plasmablastic lymphoma, Primary effusion lymphoma, Large B-cell lymphoma arising from HHV8-associated multicentric Castleman’s disease, ALK+ large B cell lymphoma, or a combination thereof.
  • a method for treating CLL in a subject comprising administering to a subject a compound of Formula (I) and an anti-CD20 therapy, which in one embodiment comprises an anti-CD20 agent.
  • the CLL is associated with low CD20 expression levels in the subject.
  • a method for treating a lymphoma in a subject comprising administering to a subject a compound of Formula (I) and an anti-CD20 therapy.
  • the lymphoma is associated with low CD20 expression levels in the subject.
  • a method for treating a non-Flodgkin’s lymphoma in a subject comprising administering to a subject a compound of Formula (I) and an anti-CD20 therapy.
  • the lymphoma is associated with low CD20 expression levels in the subject.
  • a method for treating a lymphoma in a subject comprising administering to a subject a compound of Formula (I) and an anti-CD20 therapy.
  • the lymphoma is associated with low CD20 expression levels in the subject.
  • a method for treating a diffuse large B-cell lymphoma (DLBCL) in a subject comprising administering to a subject a compound of Formula (I) and an anti- CD20 therapy.
  • the lymphoma is associated with low CD20 expression levels in the subject.
  • a method for treating a mantle cell lymphoma (MCL) in a subject comprising administering to a subject a compound of Formula (I) and an anti-CD20 therapy.
  • MCL mantle cell lymphoma
  • the lymphoma is associated with low CD20 expression levels in the subject.
  • the anti-CD20 therapy comprises an anti-CD20 agent, which in one embodiment, comprises an anti-CD20 monoclonal antibody, which in one embodiment comprises rituximab, ofatumumab, obinutuzumab, or a combination thereof.
  • low CD20 expression levels are associated with one or more Notch 1 activating mutations. In another embodiment, low CD20 expression levels are associated with one or more Notch 2 activating mutations. In another embodiment, low CD20 expression levels are associated with one or more Notch 3 activating mutations. In another embodiment, low CD20 expression levels are associated with one or more Notch 4 activating mutations.
  • the present invention provides the use of a therapeutically acceptable amount of one or more compounds or compositions as described herein for treating, suppressing or inhibiting a proliferative disease in a subject. In another embodiment, the present invention provides the use of a therapeutically effective amount of one or more compounds or compositions as described herein for treating, suppressing or inhibiting a proliferative disease in a subject. In another embodiment, the present invention provides the use of a synergistically effective amount of one or more compounds or compositions as described herein for treating, suppressing or inhibiting a proliferative disease in a subject. In another embodiment, the present invention provides the use of a synergistically therapeutically effective amount of one or more compounds or compositions as described herein for treating, suppressing or inhibiting a proliferative disease in a subject.
  • the proliferative disease comprises a Desmoid tumor.
  • the proliferative disease comprises a pre-cancerous condition or a benign proliferative disorder.
  • pre-cancerous or, alternatively,“pre-malignant” as used herein interchangeably refers to diseases, syndromes or other conditions associated with an increased risk of cancer.
  • Pre-cancer conditions in the context of the present invention include, but are not limited to: breast calcifications, vaginal intra-epithelial neoplasia, Barrett's esophagus, atrophic gastritis, dyskeratosis congenital, sideropenic dysphagia, lichen planus, oral submucous fibrosis, actinic keratosis, solar elastosis, cervical dysplasia, leukoplakia and erythroplakia.
  • the term "benign hyperproliferative disorder” as used herein refers to a condition in which there is an abnormal growth and differentiation of cells and an increase in the amount of organic tissue that results from cell proliferation.
  • the benign hyperproliferative disorder may be attributed to lack of response or inappropriate response to regulating factors, or alternatively to dysfunctional regulating factors.
  • Non-limiting examples of benign hyperproliferative disorder are psoriasis and benign prostatic hyperplasia (BPH).
  • the proliferative disease comprises a cancer.
  • the cancer comprises a solid tumor. In another embodiment, the cancer comprises a hematological malignancy.
  • a subject as described herein has cancer.
  • the term "cancer" in the context of the present invention includes all types of neoplasm whether in the form of solid or non-solid tumors and includes both malignant and premalignant conditions as well as their metastasis.
  • the cancer comprises a hematological malignancy.
  • the cancer is a carcinoma, sarcoma, myeloma, leukemia, or lymphoma.
  • the cancer is a mixed type.
  • Mixed Type cancers contain several types of cells. The type components may be within one category or from different categories. Some examples are: adenosquamous carcinoma; mixed mesodermal tumor; carcinosarcoma; teratocarcinoma.
  • the carcinoma comprises Adenoid Cystic Carcinoma (ACC). In another embodiment, the carcinoma comprises Gastro-esophageal junction carcinoma.
  • the carcinoma is an adenocarcinoma. In another embodiment, the carcinoma is a squamous cell carcinoma.
  • the sarcoma comprises osteosarcoma or osteogenic sarcoma (bone); Chondrosarcoma (cartilage); Leiomyosarcoma (smooth muscle); Rhabdomyosarcoma (skeletal muscle); Mesothelial sarcoma or mesothelioma (membranous lining of body cavities); Fibrosarcoma (fibrous tissue); Angiosarcoma or hemangioendothelioma (blood vessels); Liposarcoma (adipose tissue); Glioma or astrocytoma (neurogenic connective tissue found in the brain); Myxosarcoma (primitive embryonic connective tissue); and Mesenchymous or mixed mesodermal tumor (mixed connective tissue types).
  • the cancer comprises myeloma, which, in one embodiment, is cancer that originates in the plasma cells of bone marrow.
  • the plasma cells produce some of the proteins found in blood.
  • the cancer comprises multiple myeloma.
  • the cancer comprises leukemia ("non-solid tumor” or "blood cancer”), which in one embodiment, is a cancer of the bone marrow (the site of blood cell production).
  • leukemia comprises myelogenous or granulocytic leukemia (malignancy of the myeloid and granulocytic white blood cell series); Lymphatic, lymphocytic, or lymphoblastic leukemia (malignancy of the lymphoid and lymphocytic blood cell series); and Polycythemia vera or erythremia (malignancy of various blood cell products, but with red cells predominating).
  • the cancer comprises T-cell acute lymphoblastic leukemia (T- ALL). In another embodiment, the cancer comprises T-lymphoblastic leukemia/lymphoma (TLL). In another embodiment, the cancer comprises Chronic Lymphocytic Leukemia (CLL).
  • the cancer comprises a lymphoma.
  • the lymphoma comprises an extranodal lymphoma.
  • the lymphoma comprises a Hodgkin lymphoma.
  • the lymphoma comprises a Non-Hodgkin lymphoma.
  • the lymphoma comprises a marginal zone B cell lymphoma, a diffuse large B cell lymphoma, or a mantle cell lymphoma.
  • the cancer is dependent upon Notch activation.
  • the cancer comprises a Notch-activating mutation.
  • the cancer is not dependent upon Notch activation.
  • a cancer as described herein comprises a Notch activating genetic alteration. In another embodiment, a cancer as described herein comprises a Notch activating alteration. In another embodiment, a cancer as described herein comprises a Notch activating mutation. In another embodiment, a cancer as described herein comprises a Notch activating genetic mutation. In another embodiment, a cancer as described herein comprises a Notch mutation. In another embodiment, a cancer as described herein comprises a Notch altering mutation.
  • Notch activating genetic alterations comprise a mutation in one or more Notch related genes.
  • the mutation in one or more Notch-related genes induces a gain of function (GOF) in Notch activity.
  • GEF gain of function
  • the mutation in one or more Notch-related genes comprises a missense mutation. In another embodiment, the mutation in one or more Notch-related genes comprises a nonsense mutation. In another embodiment, the mutation in one or more Notch-related genes comprises an insertion mutation. In another embodiment, the mutation in one or more Notch- related genes comprises a deletion mutation. In another embodiment, the mutation in one or more Notch-related genes comprises a duplication mutation. In another embodiment, the mutation in one or more Notch-related genes comprises a frameshift mutation. In another embodiment, the mutation in one or more Notch-related genes comprises a repeat expansion. In another embodiment, the mutation in one or more Notch-related genes comprises a fusion.
  • the cancer comprises astrocytoma, bladder cancer, breast cancer, cholangiocarcinoma (CCA), colon cancer, colorectal cancer, colorectal carcinoma, epithelial carcinoma, epithelial ovarian cancers, fibrosarcoma, gall bladder cancer, gastric cancer, glioblastoma, glioma, head and neck cancer, hepatocellular carcinoma, kidney cancer, liver cancer, lung cancer including non-small cell lung cancer (NSCLC), malignant fibrous histiocytoma (MFH), malignant pleural mesothelioma (MPM), medulloblastoma, melanoma, mesothelioma, neuroblastoma, osteosarcoma, ovarian adenocarcinoma, ovarian cancer, pancreatic adenocarcinoma, pancreatic cancer, prostate cancer, renal cell carcinoma (RCC), rhabdomyosarcoma, seminal
  • cancer includes the above categories of carcinoma, sarcoma, myeloma, leukemia, lymphoma and mixed type tumors.
  • cancer includes: lymphoproliferative disorders, breast cancer, ovarian cancer, prostate cancer, cervical cancer, endometrial cancer, lung cancer, bone cancer, liver cancer, stomach cancer, bladder cancer, colon cancer, colorectal cancer, pancreatic cancer, cancer of the thyroid, head and neck cancer, cancer of the central nervous system, brain cancer, cancer of the peripheral nervous system, skin cancer, kidney cancer, as well as metastases of all the above.
  • the term may refer to: hepatocellular carcinoma, hematoma, hepatoblastoma, rhabdomyosarcoma, esophageal carcinoma, thyroid carcinoma, ganglioblastoma, glioblastoma, fibrosarcoma, myxosarcoma, liposarcoma, chondrosarcoma, osteogenic sarcoma, chordoma, angiosarcoma, endotheliosarcoma, Ewing's tumor, leimyosarcoma, rhabdotheliosarcoma, invasive ductal carcinoma, papillary adenocarcinoma, melanoma, squamous cell carcinoma, basal cell carcinoma, adenocarcinoma (well differentiated, moderately differentiated, poorly differentiated or undifferentiated), renal cell carcinoma, hypernephroma, hypernephroid adenocarcinoma, bile
  • the administration of the combined compositions as described herein reduces growth of the cells of a solid tumor or hematological malignancy by 40%, 50%, 60%, 70%, 80%, 90% or 95% compared to growth of the cells of the solid tumor or hematological malignancy that have not been treated with the combined compositions, i.e. have been treated with either one of the compositions, have been treated via a different cancer treatment, or have not been treated.
  • the present invention provides methods of increasing or lengthening survival of a subject having a neoplasia.
  • neoplasia refers to a disease characterized by the pathological proliferation of a cell or tissue and its subsequent migration to or invasion of other tissues or organs. Neoplasia growth is typically uncontrolled and progressive, and occurs under conditions that would not elicit, or would cause cessation of, multiplication of normal cells.
  • Neoplasias can affect a variety of cell types, tissues, or organs, including but not limited to an organ selected from the group consisting of bladder, colon, bone, brain, breast, cartilage, glia, esophagus, fallopian tube, gallbladder, heart, intestines, kidney, liver, lung, lymph node, nervous tissue, ovaries, pleura, pancreas, prostate, skeletal muscle, skin, spinal cord, spleen, stomach, testes, thymus, thyroid, trachea, urogenital tract, ureter, urethra, uterus, and vagina, or a tissue or cell type thereof.
  • Neoplasias include cancers, such as sarcomas, carcinomas, or plasmacytomas (malignant tumor of the plasma cells).
  • a subject as described herein is being treated with or has been previously treated with radiation therapy, chemotherapy, transplantation, immunotherapy, hormone therapy, or photodynamic therapy.
  • a method for treating cancer comprising administering to a mammal in need thereof a combination of a compound of Formula (I), an anti-CD20 agent, and optionally, one or more additional anti-cancer agents.
  • the additional anti-cancer agent comprises Chlorambucil, Fludarain, Pentostatin, Ciclophosphamide, F1DMP, Bendamustine, or a combination thereof.
  • the cancer comprises CLL.
  • the additional anti-cancer agent comprises cisplatin, dasatinib, paclitaxel, tamoxifen, or a combination thereof.
  • the“additional anti-cancer agent” refers to a drug selected from any one or more of the following: alkylating agents (including nitrogen mustards, alkyl sulfonates, nitrosoureas, ethylenimine derivatives, and triazenes); anti-angiogenics (including matrix metalloproteinase inhibitors); antimetabolites (including adenosine deaminase inhibitors, folic acid antagonists, purine analogues, and pyrimidine analogues); antibiotics or antibodies (including monoclonal antibodies, anthracyclines); aromatase inhibitors; cell-cycle response modifiers; enzymes; farnesyl-protein transferase inhibitors; hormonal and antihormonal agents and steroids (including synthetic analogs, glucocorticoids, estrogens/anti-estrogens [e.g., SERMs], androgens/anti-androgens, progestins, progester
  • a method for treating cancer comprising administering to a mammal in need thereof a combination of a compound of Formula (I) and an additional anti-cancer agent, which is one embodiment, comprises an anti-CD20 agent; administering a glucocorticoid; and optionally, one or more additional anti-cancer agents.
  • a suitable glucocorticoid is dexamethasone.
  • a method for treating cancer comprising administering to a mammal in need thereof a combination of a compound of Formula (I) and an additional anti-cancer agent, which is one embodiment, comprises an anti-CD20 agent; administering carboplatin; and optionally, one or more additional anti-cancer agents.
  • an additional anti-cancer agent which is one embodiment, comprises an anti-CD20 agent; administering carboplatin; and optionally, one or more additional anti-cancer agents.
  • references made in the singular may also include the plural.
  • “a” and“an” may refer to either one, or one or more.
  • administering refers to bringing in contact with a compound of the present invention.
  • the compositions are applied locally.
  • the compositions are applied systemically. Administration can be accomplished to cells or tissue cultures, or to living organisms, for example humans.
  • parenteral administration refers to delivering one or more compounds or compositions to a subject parenterally, enterally, or topically.
  • parenteral administration include, but are not limited to, intravenous, intramuscular, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcuticular, intraarticulare, subcapsular, subarachnoid, intraspinal and intrasternal injection and infusion.
  • enteral administration include, but are not limited to oral, inhalation, intranasal, sublingual, and rectal administration.
  • topical administration include, but are not limited to, transdermal and vaginal administration.
  • an agent or composition is administered parenterally, optionally by intravenous administration or oral administration to a subject.
  • a composition of the present invention comprises a pharmaceutically acceptable composition.
  • pharmaceutically acceptable is employed herein to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
  • a composition of the present invention is administered in a therapeutically effective amount.
  • a“therapeutically effective amount” is intended to include an amount of a compound of the present invention alone or an amount of the combination of compounds claimed or an amount of a compound of the present invention in combination with other active ingredients effective to act as an inhibitor to a NOTCH receptor, effective to inhibit gamma secretase, or effective to treat or prevent proliferative diseases such as cancer.
  • a "therapeutically effective amount" of a composition of the invention is that amount of composition which is sufficient to provide a beneficial effect to the subject to which the composition is administered.
  • “treating” or“treatment” cover the treatment of a disease-state in a mammal, particularly in a human, and include: (a) preventing the disease-state from occurring in a mammal, in particular, when such mammal is predisposed to the disease-state but has not yet been diagnosed as having it; (b) inhibiting the disease-state, i.e., arresting its development; and/or (c) relieving the disease-state, i.e., causing regression of the disease state.
  • treating includes induction therapy. In another embodiment, treating includes treating patients who are not responsive or refractory to anti-CD20 therapy.
  • “treating” refers to both therapeutic treatment and prophylactic or preventative measures, wherein the object is to prevent or lessen the targeted pathologic condition or disorder as described hereinabove.
  • treating may include directly affecting or curing, suppressing, inhibiting, preventing, reducing the severity of, delaying the onset of, reducing symptoms associated with the disease, disorder or condition, or a combination thereof
  • “treating” refers inter alia to delaying progression, expediting remission, inducing remission, augmenting remission, speeding recovery, increasing efficacy of or decreasing resistance to alternative therapeutics, or a combination thereof
  • “preventing” refers, inter alia, to delaying the onset of symptoms, preventing relapse to a disease, decreasing the number or frequency of relapse episodes, increasing latency between symptomatic episodes, or a combination thereof
  • “suppressing” or“inhibiting” refers inter alia to reducing the severity of symptoms
  • the term“decreasing the size of the tumor” as used herein is assessed using the“Response Evaluation Criteria In Solid Tumors” (RECIST).
  • RECIST measures reduction in tumor size by measuring the longest dimension of a target lesion.
  • the target lesion is selected on the basis of its size (lesion with the longest diameter) and its suitability for accurate repeated measurements (either by imaging techniques or clinically).
  • all other lesions (or sites of disease) are identified as non-target lesions and are also recorded at baseline. Measurements of these lesions are not required, but the presence or absence of each is noted throughout follow-up.
  • the term“decreasing the volume of the tumor” as used herein is assessed using the radiological tumor response evaluation criteria.
  • the tumor is measured in two dimensions its maximum diameter (width) in the translation plane and its largest perpendicular diameter on same image (thickness), according to the World Health Organization (WHO).
  • WHO World Health Organization
  • a subject as described herein is human.
  • the subject is mammalian.
  • the subject is a primate, which in one embodiment, is a non-human primate.
  • the subject is murine, which in one embodiment is a mouse, and, in another embodiment is a rat.
  • the subject is canine, feline, bovine, equine, caprine, ovine, porcine, simian, ursine, vulpine, or lupine.
  • the subject is a chicken or fish.
  • the compositions as described herein comprise the components of the composition (i.e., one or more anti-cancer agents and one or more gamma secretase inhibitors comprising a compound of Formula (I)) as described herein.
  • the compositions as described herein consist of the components of the composition (i.e., one or more anti cancer agents and one or more gamma secretase inhibitors comprising a compound of Formula (I)) as described herein.
  • the compositions as described herein consist essentially of the components of the composition (i.e., one or more anti-cancer agents and one or more gamma secretase inhibitors comprising a compound of Formula (I)) as described herein.
  • compositions and methods of the present invention comprising the elements or steps as described herein may, in another embodiment, consist of those elements or steps, or in another embodiment, consist essentially of those elements or steps.
  • the term“comprise” refers to the inclusion of the indicated active agents, such as the anti-cancer agents and the gamma secretase inhibitor, as well as inclusion of other active agents, and pharmaceutically or physiologically acceptable carriers, excipients, emollients, stabilizers, etc., as are known in the pharmaceutical industry.
  • the term“consisting essentially of’ refers to a composition, whose only active ingredients are the indicated active ingredients.
  • the term“consisting essentially of’ may refer to components which facilitate the release of the active ingredient.
  • the term“consisting” refers to a composition, which contains the active ingredients and a pharmaceutically acceptable carrier or excipient.
  • the administration of the anti-cancer agents occurs prior to, concurrent with, or following the administration of the compound of Formula (I).
  • the administration of the anti-cancer agents occurs at the same site as the administration of the compound of Formula (I).
  • the compound of Formula (I) is administered daily. In another embodiment, the compound of Formula (I) is administered 2 or 3 times per day. In another embodiment, the compound of Formula (I) is administered twice weekly. In another embodiment, the compound of Formula (I) is administered three, four, five, or six times per week. In another embodiment, the compound of Formula (I) is administered weekly. In another embodiment, the compound of Formula (I) is administered biweekly. In another embodiment, the compound of Formula (I) is administered once every three weeks. In another embodiment, the anti-CD20 agent is administered once every three weeks. In one embodiment, the anti-CD20 agent is administered until inhibition of disease progression is detected.
  • the compound of Formula (I) is admini tered several days before and after the administration of the anti-cancer agent. In one embodiment, the compound of Formula (I) is administered 1, 2, 3, 4, or 5 days prior to the administration of the anti-cancer agent. In one embodiment, the compound of Formula (I) is administered 1 , 2, 3, 4, or 5 days subsequent to the administration of the anti-cancer agent. In another embodiment, the compound of Formula (I) is administered one day before and up to 9 days following anti-cancer agent administration. In another embodiment, the compound of Formula (I) is administered one day before and on days 1, 8, and 9 following anti-cancer agent administration. In another embodiment, the compound of Formula (I) is administered one day before and 9 days following anti-cancer agent administration. In another embodiment, the compound of Formula (I) is administered one day before and daily for 9 days following anti-cancer agent administration. In another embodiment, the compound of Formula (I) is administered one day before and on day 9 following anti-cancer agent administration.
  • compositions of the present invention are administered at least once during a treatment cycle. In some embodiments, the compositions of the present invention are administered to the subject on the same days. In some embodiments, the compositions of the present invention are administered to the subject on the different days. In some embodiments, one or more compositions of the present invention are administered to the subject on the same days and on different days according to treatment schedules.
  • one or more compositions of the present invention are administered to the subject over one or more treatment cycles.
  • a treatment cycle can be at least two, at least three, at least four, at least five, at least six, at least seven, at least 14, at least 21, at least 28, at least 48, or at least 96 days or more.
  • a treatment cycle is 28 days.
  • the compositions are administered over the same treatment cycle or concurrently over different treatment cycles assigned for each composition.
  • the treatment cycle is determined by a health care professional based on conditions and needs of the subject.
  • a composition is administered on at least one day, at least two days, at least three days, at least four days, at least five days, at least six days, at least seven days, at least eight days, at least nine days, at least ten days, at least eleven days, at least twelve days, at least 13 days, at least 14 days, at least 21 days, or all 28 days of a 28 day treatment cycle.
  • a composition is administered to a subject once a day.
  • a composition is administered twice a day.
  • a composition is administered more than twice a day.
  • one or more of the compositions as described herein are administered once per day.
  • one or more of the compositions as described herein are administered twice per day. In another embodiment, one or more of the compositions as described herein are administered three times per day. In another embodiment, one or more of the compositions as described herein are administered four times per day. In another embodiment, one or more of the compositions as described herein are administered once every two days, once every three days, twice a week, once a week, once every 2 weeks, once every 3 weeks.
  • one or more of the compositions as described herein are administered for 7 days to 28 days. In another embodiment, one or more of the compositions as described herein are administered for 7 days to 8 weeks. In another embodiment, one or more of the compositions as described herein are administered for 7 days to 50 days. In another embodiment, one or more of the compositions as described herein are administered for 7 days to six months. In another embodiment, one or more of the compositions as described herein are administered for 7 days to one and half years. In another embodiment, one or more of the compositions as described herein are administered for 14 days to 12 months. In another embodiment, one or more of the compositions as described herein are administered for 14 days to 3 years. In another embodiment, one or more of the compositions as described herein are administered for several years. In another embodiment, one or more of the compositions as described herein are administered for one month to six months.
  • one or more of the compositions as described herein are administered for 7 days. In another embodiment, one or more of the compositions as described herein are administered for 14 days. In another embodiment, one or more of the compositions as described herein are administered for 21 days. In another embodiment, one or more of the compositions as described herein are administered for 28 days. In another embodiment, one or more of the compositions as described herein are administered for 50 days. In another embodiment, one or more of the compositions as described herein are administered for 56 days. In another embodiment, one or more of the compositions as described herein are administered for 84 days. In another embodiment, one or more of the compositions as described herein are administered for 90 days. In another embodiment, one or more of the compositions as described herein are administered for 120 days.
  • compositions disclosed herein are administered once to a subject in need thereof with a mild acute condition. In some embodiments, a composition disclosed herein is administered more than once to a subject in need thereof with a moderate or severe acute condition. In the case wherein the subject's condition does not improve, upon the doctor's discretion the composition may be administered chronically, that is, for an extended period of time, including throughout the duration of the subject's life in order to ameliorate or otherwise control or limit the symptoms of the subject's disease or condition.
  • the composition may administered continuously; or, the dose of drug being administered may be temporarily reduced or temporarily suspended for a certain length of time (i.e., a "drug holiday").
  • the length of the drug holiday varies between 2 days and 1 year, including by way of example only, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 10 days, 12 days, 15 days, 20 days, 28 days, 35 days, 50 days, 70 days, 100 days, 120 days, 150 days, 180 days, 200 days, 250 days, 280 days, 300 days, 320 days, 350 days, and 365 days.
  • the dose reduction during a drug holiday may be from 10%- 100%, including by way of example only 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, and 100%.
  • the present invention further comprises combinations of the compositions of the present invention and, optionally, one or more additional agents in kit form, e.g., where they are packaged together or placed in separate packages to be sold together as a kit, or where they are packaged to be formulated together.
  • the kit comprises a therapeutic or prophylactic composition containing an effective amount of an inhibitor of CD20 in unit dosage form and an effective amount of the compound of Formula (I), as described herein.
  • the cells further express at least one co-stimulatory ligand.
  • the kit comprises a sterile container which contains therapeutic or prophylactic agents; such containers can be boxes, ampules, bottles, vials, tubes, bags, pouches, blister-packs, or other suitable container forms known in the art.
  • Such containers can be made of plastic, glass, laminated paper, metal foil, or other materials suitable for holding medicaments.
  • the composition(s) are provided together with instructions for administering the composition(s) to a subject having or at risk of developing a neoplasia (e.g., multiple myeloma).
  • the instructions will generally include information about the use of the composition for the treatment or prevention of a neoplasia (e.g., multiple myeloma).
  • the instructions include at least one of the following: description of the therapeutic agent; dosage schedule and administration for treatment or prevention of a neoplasia (e.g., multiple myeloma) or symptoms thereof; precautions; warnings; indications; counter-indications; overdosage information; adverse reactions; animal pharmacology; clinical studies; and/or references.
  • the instructions may be printed directly on the container (when present), or as a label applied to the container, or as a separate sheet, pamphlet, card, or folder supplied in or with the container.
  • GSIs g-secretase inhibitors
  • Compound 1 or Compound 22 were added to the cell cultures at concentrations of 10, 1, 0.5, 0.1, 0.01, 0.OOImM. Following 7 days of incubation at 37°C, the cells were collected and stained with anti CD20 antibody and cell surface CD20 levels were immediately analyzed by flow cytometry (FACS analysis).
  • GSIs g-secretase inhibitors
  • a further study can be conducted to show the efficacy of treating patients with a disease comprising a NOTCH activating mutation, in accordance with methods described herein.
  • the study will involve treating patients with a B cell lymphoma or a B cell leukemia with identifed Notch mutations wherein the level of CD20 expression is decreased.
  • the study will include 2 arms: in arm A, the patients with B cell Lymphoma or leukemia are treated wth the standard of care, RCHOP (Rituximab; cyclophosphamide; doxorubicin (hydroxydaunomycin); vincristine (Oncovin®); prednisolone).
  • the endpoints of the study will include observing rate of complete remission, partial remission and stable disease, time of progression, progression free survival and overall survival and rate of Minimal Residual Disease (MDR).
  • MDR Minimal Residual Disease

Abstract

The present invention provides compositions comprising bisfluoroalkyl-1,4-benzodiazepinone compounds, including compounds of Formula (I) or prodrugs thereof; (I), in combination with an anti-CD20 agent or other anti-CD20 therapy, and methods of use thereof for treating diseases and disorders such as cancer.

Description

COMPOSITIONS COMPRISING CD20 INHIBITORS AND BISFLUOROALKYL-1,4- BENZODIAZEPINONE COMPOUNDS AND METHODS OF USE THEREOF
FIELD OF THE INVENTION
[001] The present invention provides compositions comprising bisfluoroalkyl-l ,4- benzodiazepinone compounds, including compounds of Formula (I) or prodrugs thereof;
Figure imgf000003_0001
in combination with an anti-CD20 agent, or other anti-CD20 therapy, and methods of use thereof for treating diseases and disorders such as cancer.
BACKGROUND OF THE INVENTION
[002] Benzodiazepinone compounds as Notch inhibitors useful for the treatment of conditions related to the Notch pathway, such as cancer and other proliferative diseases are known. Recent studies have suggested that NOTCH activating mutations, including, for example, NOTCH1 activating mutations, can be associated with low CD20 levels in some diseases, such as Chronic Lymphocytic Leukemia (CLL), resulting in resistance to anti-CD20 therapies and poorer prognosis. Thus, there remains a need in the art for increasing the efficacy of anti-CD20 therapies and providing better treatment methods in patients having such diseases.
SUMMARY OF THE INVENTION
[003] The present invention provides a composition comprising one or more compounds represented by the structure of Formula (I):
Figure imgf000003_0002
and/or at least one salt thereof, wherein:
Ri is -CH2CF3 or -CH2CH2CF3; R2 is -CH2CF3, -CH2CH2CF3, or -CH2CH2CH2CF3 ;
R3 is H, -CH3 or Rx;
R4 is H or Ry;
Rx
Figure imgf000004_0001
Ry is: -SCH2CH(NH2)C(0)0H, -SCH2CH(NH2)C(0)0H3,
or -SCH2CH(NH2)C(0)0C(CH3)3;
Ring A is phenyl or pyridinyl;
each Ra is independently F, Cl, -CN, -OCH3, Ci-3 alkyl, -CH2OH, -CF3,
cyclopropyl, -OCFl3, -O(cyclopropyl) and/or -NFlCF[2CF[2OCF[3;
each Rb is independently F, Cl, -CH3, -CH2OH, -CF3, cyclopropyl, and/or -OCFl3;
y is zero, 1 or 2; and
z is zero, 1 , or 2
in combination with an anti-CD20 agent.
[004] The present invention also provides a method of increasing the efficacy of an anti-CD20 therapy in a subject, comprising the step of administering to said subject a first composition comprising one or more compounds represented by the structure of Formula (I):
Figure imgf000004_0002
and/or at least one salt thereof, wherein:
Ri is -CH2CF3 or -CH2CH2CF3;
R2 is -CH2CF3, -CH2CH2CF3, or -CH2CH2CH2CF3 ;
R3 is H, -CFl3 or Rx;
R4 is Fl or Ry; Rx
is:
)2)
Figure imgf000005_0001
Figure imgf000005_0002
Ry is: -SCH2CH(NH2)C(0)0H, -SCH2CH(NH2)C(0)0H3,
or -SCH2CH(NH2)C(0)0C(CH3)3;
Ring A is phenyl or pyridinyl;
each Ra is independently F, Cl, -CN, -OCH3, C1-3 alkyl, -CH2OH, -CF3,
cyclopropyl, -OCH3, -O(cyclopropyl) and/or -NHCH2CH2OCH3;
each Rb is independently F, Cl, -CH3, -CH2OH, -CF3, cyclopropyl, and/or -OCH3;
y is zero, 1 or 2; and
z is zero, 1 , or 2,
wherein the administering increases the efficacy of the anti-CD20 therapy in the subject. [005] The present invention also provides a method of treating a disease comprising a NOTCH1 activating mutation in a subject, the method comprising the step of administering to said subject a first composition comprising one or more compounds represented by the structure of Formula (I):
Figure imgf000005_0003
and/or at least one salt thereof, wherein:
Ri is -CH2CF3 or -CH2CH2CF3;
R2 is -CH2CF3, -CH2CH2CF3, or -CH2CH2CH2CF3;
R3 is H, -CH3 or Rx;
R4 is Fl or Ry;
Rx
Figure imgf000006_0001
Ry is: -SCH2CH(NH2)C(0)0H, -SCH2CH(NH2)C(0)0H3,
or -SCH2CH(NH2)C(0)0C(CH3)3;
Ring A is phenyl or pyridinyl;
each Ra is independently F, Cl, -CN, -OCH3, Ci-3 alkyl, -CH2OH, -CF3,
cyclopropyl, -OCFl3, -O(cyclopropyl) and/or -NFlCF[2CF[2OCF[3;
each Rb is independently F, Cl, -CH3, -CFl2OF[, -CF3, cyclopropyl, and/or -OCFl3;
y is zero, 1 or 2; and
z is zero, 1 , or 2
and a second composition comprising an anti-CD20 monoclonal antibody.
[006] The present invention also provides a method of treating Chronic Lymphocytic Leukemia (CLL) or a lymphoma associated with low CD20 expression levels in a subject, the method comprising the step of administering to said subject a first composition comprising one or more compounds represented by the structure of Formula (I):
Figure imgf000006_0002
and/or at least one salt thereof, wherein:
Ri is -CH2CF3 or -CH2CH2CF3;
R2 is -CH2CF3, -CH2CH2CF3, or -CH2CH2CH2CF3 ;
R3 is H, -CFl3 or Rx;
R4 is Fl or Ry;
Rx is:
)2)
Figure imgf000007_0001
Figure imgf000007_0002
Ry is: -SCH2CH(NH2)C(0)0H, -SCH2CH(NH2)C(0)0H3,
or -SCH2CH(NH2)C(0)0C(CH3)3;
Ring A is phenyl or pyridinyl;
each Ra is independently F, Cl, -CN, -OCH3, Ci-3 alkyl, -CH2OH, -CF3,
cyclopropyl, -OCH3, -O(cyclopropyl) and/or -NHCH2CH2OCH3;
each Rb is independently F, Cl, -CH3, -CH2OH, -CF3, cyclopropyl, and/or -OCH3;
y is zero, 1 or 2; and
z is zero, 1 , or 2
and a second composition comprising rituximab.
BRIEF DESCRIPTION OF THE DRAWINGS
[007] The subject matter regarded as the invention is particularly pointed out and distinctly claimed in the concluding portion of the specification. The invention, however, both as to organization and method of operation, together with objects, features, and advantages thereof, may best be understood by reference to the following detailed description when read with the accompanying drawings in which:
[008] Figure 1A. Levels of CD20 in Lymphoma Cell Lines after treatment with g-secretase inhibitor (GSI), Compound 1. Cells from five different lymphoma cell lines (SP49 (MCL with Notch4 GOF); Toledo (DLBCL); RC (Double Hit DLBCL - MYC, BCL2); SUDHL-4 (DLBCL); and SUDHL-6 (DLBCL)) were treated for 7 days with 0, lnM, lOnM, lOOnM, 500nM, lOOOnM, and 1 OOOOnM of the GSI compound 1. Cell surface CD20 levels were observed by flow cytometry (FACS analysis).
[009] Figure IB. Levels of CD20 in Lymphoma Cell Lines after treatment with g-secretase inhibitor (GSI), Compound 22. Cells from five different lymphoma cell lines (SP49 (MCL with Notch4 GOF); Toledo (DLBCL); RC (Double Hit DLBCL - MYC, BCL2); SUDHL-4 (DLBCL); and SUDHL-6 (DLBCL)) were treated for 7 days with 0, lnM, lOnM, lOOnM, 500nM, lOOOnM, and 1 OOOOnM of the GSI compound 2. Cell surface CD20 levels were observed by flow cytometry (FACS analysis).
[0010] Figure 2A. Levels of CD20 in Lymphoma Cell Lines after treatment with g-secretase inhibitor (GSI), Compound 1. Cells from three different lymphoma cell lines (SUDHL-4 (DLBCL); Rec-l (MCL); and SP49 (MCL)) were treated for 7 days with 0, IhM, IOhM, IOOhM, 500nM, lOOOnM, and lOOOOnM of Compound 1. * indicates missing data point. Cell surface CD20 levels were observed by flow cytometry (FACS analysis).
[0011] Figure 2B. Levels of CD20 in Lymphoma Cell Lines after treatment with g-secretase inhibitor (GSI), Compound 22. Cells from three different lymphoma cell lines (SUDHL-4 (DLBCL); Rec-l (MCL); and SP49 (MCL)) were treated for 7 days with 0, IhM, IOhM, lOOnM, 500nM, lOOOnM, and lOOOOnM of Compound 22. Cell surface CD20 levels were observed by flow cytometry (FACS analysis).
[0012] Figures 3A-3B. Effect of g-secretase inhibitor (GSI) Compound 1 on viability in lymphoma cells. Cells from three different lymphoma cell lines (SUDHL-4 (DLBCL); Rec-l (MCL); and SP49 (MCL)) were treated for 7 days with different concentrations of GSIs (Figure 3A - Compound 1 ; Figure 3B - Compound 22). Percent viability was determined by FACS analysis (FSC/SSC).
DETAILED DESCRIPTION OF THE PRESENT INVENTION
[0013] In the following detailed description, numerous specific details are set forth in order to provide a thorough understanding of the invention. However, it will be understood by those skilled in the art that the present invention may be practiced without these specific details. In other instances, well- known methods, procedures, and components have not been described in detail so as not to obscure the present invention.
[0014] In one embodiment, compositions of the present invention or for use in the methods of the present invention comprise one or more gamma secretase inhibitors. In one embodiment, the gamma secretase inhibitor comprises a bisfluoroalkyl-l,4-benzodiazepinone compound.
[0015] In one embodiment, compositions of the present invention or for use in the methods of the present invention comprise one or more NOTCH inhibitors. In one embodiment, the NOTCH inhibitor comprises a bisfluoroalkyl-l,4-benzodiazepinone compound.
Bisfluoroalkyl-l,4-benzodiazepinone Compounds
[0016] In one embodiment, the present invention provides compositions comprising compounds represented by the structure of Formula (I):
Figure imgf000009_0001
and/or at least one salt thereof, wherein:
Ri is -CH2CF3 or -CH2CH2CF3;
R2 is -CH2CF3, -CH2CH2CF3, or -CH2CH2CH2CF3 ;
R3 is H, -CH3 or Rx;
R4 is Fl or Ry;
Rx
is: -CH20C(0)CH(CH3)NH2, -CH20C(0)CH(NH2)CH(CH3)2, -CH20C(0)CH((CH(
Figure imgf000009_0002
Ry is: -SCH2CH(NH2)C(0)0H, -SCH2CH(NH2)C(0)0H3,
or -SCH2CH(NH2)C(0)0C(CH3)3;
Ring A is phenyl or pyridinyl;
each Ra is independently F, Cl, -CN, -OCH3, C1-3 alkyl, -CH2OH, -CF3,
cyclopropyl, -OCH3, -O(cyclopropyl) and/or -NHCH2CH2OCH3;
each Rb is independently F, Cl, -CH3, -CH2OH, -CF3, cyclopropyl, and/or -OCH3; y is zero, 1 or 2; and
z is zero, 1, or 2.
[0017] In one embodiment, the present invention provides compositions comprising compounds represented by the structure of Formula (II):
Figure imgf000010_0001
wherein R3 is H or -CH3; and y is zero or 1.
[0018] In one embodiment, the present invention provides compositions comprising compounds of Formula (III):
Figure imgf000010_0002
or prodrugs or salts thereof; wherein:
Ri is -CH2CF3 or -CH2CH2CF3;
R2 is -CH2CF3, -CH2CH2CF3, or -CH2CH2CH2CF3 ;
R3 is Fl or -CH3;
each Ra is independently F, Cl, -CN, -OCH3, and/or -NHCH2CH2OCH3; and
y is zero, 1 , or 2.
[0019] In one embodiment, R2 is -CH2CF3 or -CH2CH2CF3. In one embodiment, Ri is -CH2CF3 or - CH2CH2CF3 and R2 is -CH2CF3 or -CH2CH2CF3. In another embodiment, Ri is -CH2CH2CF3 and R2 is -CH2CH2CF3. In one embodiment, y is zero or 1. In another embodiment, y is 1 or 2. In another embodiment, y is 1 or 2.
[0020] In one embodiment, the compound of Formula (III) comprises: (2R,3S)— N-((3S)-l-methyl- 2-oxo-5-phenyl-2,3-dihydro-lH-l,4-benzodiazepin-3-yl)-2,3-bis(3,3,3-trifluoropropyl)succinamide (1)
Figure imgf000011_0001
[0021] In another embodiment, the compound of Formula (III) comprises: (2R,3S)— N-((3S)-2-oxo- 5-phenyl-2,3-dihydro-lFl-l,4-benzodiazepin-3-yl)-2,3-bis(3,3,3-trifluoropropyl)succinamide (2)
Figure imgf000011_0002
[0022] In another embodiment, the compound of Formula (III) comprises: (2R,3S)— N-((3S)-l- methyl-2-oxo-5-phenyl-2,3-dihydro-lFl-l,4-benzodiazepin-3-yl)-2-(2,2,2-trifluoroethyl)-3-(3,3,3- trifluoropropyl)succinamide (3);
(3)
Figure imgf000011_0003
[0023] In another embodiment, the compound of Formula (III) comprises: (2R,3S)— N-((3S)-l- methyl-2-oxo-5-phenyl-2,3-dihydro-lH-l,4-benzodiazepin-3-yl)-3-(2,2,2-trifluoroethyl)-2-(3,3,3- trifluoropropyl)succinamide (4);
Figure imgf000011_0004
[0024] In another embodiment, the compound of Formula (III) comprises: (2R,3S)— N-((3S)-l- (2]¾)methyl-2-oxo-5-phenyl-2,3-dihydro-lF[-l,4-benzodiazepin-3-yl)-2,3-bis(3,3,3- trifluoropropyl)succinamide (5);
Figure imgf000012_0001
[0025] In another embodiment, the compound of Formula (III) comprises a compound of Formula
(VI):
Figure imgf000012_0002
which in one embodiment, comprises (2R,3S)— N-((3S)-7-chloro-l-methyl-2-oxo-5-phenyl-2,3- dihydro-lH-l,4-benzodiazepin-3-yl)-2,3-bis(3,3,3-trifluoropropyl)succinamide (6), i.e. Y=H and Z=Cl; (2R,3 S)— N-((3S)-8-methoxy- 1 -methyl-2-oxo-5 -phenyl-2, 3-dihydro- 1 H- 1 ,4-benzodiazepin- 3-yl)-2,3-bis(3,3,3-trifluoropropyl)succinamide (7), i.e. U=0O¾ and Z=H; (2R,3S)— N-((3S)-8- fluoro-l-methyl-2-oxo-5-phenyl-2,3-dihydro-lH-l,4-benzodiazepin-3-yl)-2,3-bis(3,3,3- trifluoropropyl)succinamide (8), i.e. Y=F and Z=H; (2R,3S)— N-((3S)-7-methoxy-l-methyl-2-oxo- 5-phenyl-2,3-dihydro-lH-l,4-benzodiazepin-3-yl)-2,3-bis(3,3,3-trrfluoropropyl)succinamide (9), Y=H and Z=OCl¾; (2R,3S)— N-((3S)-7-fluoro-l-methyl-2-oxo-5-phenyl-2,3-dihydro-lH-l ,4- benzodiazepin-3-yl)-2,3-bis(3,3,3-trifluoropropyl)succinamide (10), i.e. Y=H and Z=F; or (2R,3S)— N-((3S)-8-chloro-l-methyl-2-oxo-5-phenyl-2,3-dihydro-lFl-l,4-benzodiazepin-3-yl)-2,3-bis(3,3,3- trifluoropropyl)succinamide (11), i.e. Y=Cl and Z=FL
[0026] In another embodiment, the compound of Formula (III) comprises a compound of Formula (VII):
Figure imgf000013_0001
which in one embodiment, comprises (2R,3S)— N-((3S)-9-methoxy-2-oxo-5-phenyl-2,3-dihydro- lH-l,4-benzodiazepin-3-yl)-2,3-bis(3,3,3-trifluoropropyl)succinamide (12), i.e. X=OCH3, Y=H and Z=H; (2R,3S)— N-((3S)-8-methoxy-2-oxo-5-phenyl-2,3-dihydro-lH-l,4-benzodiazepin-3-yl)-2,3- bis(3,3,3-tifluoropropyl)succinamide (13), i.e. X=H, Y=OCH3 and Z=H; (2R,3S)— N-((3S)-7- methoxy-2-oxo-5-phenyl-2, 3-dihydro- 1 H- 1 ,4-benzodiazepin-3-yl)-2,3-bis(3,3,3- trifluoropropyl)succinamide (14), i.e. X=H, Y=H and Z=OCH3; (2R,3S)— N-((3S)-8-cyano-9- methoxy-2-oxo-5-phenyl-2, 3-dihydro- 1 H- 1 ,4-benzodiazepin-3-yl)-2,3-bis(3,3,3- trifluoropropyl)succinamide (15), i.e. X=OCH3, Y=CN and Z=H; (2R,3S)— N-((3S)-8,9-dichloro-2- oxo-5-phenyl-2,3-dihydro-lH-l,4-benzodiazepin-3-yl)-2,3-bis(3,3,3-trifluoropropyl)succinamide (16), i.e. X=Cl, Y=Cl and Z=H; (2R,3S)— N-((3S)-9-fluoro-2-oxo-5-phenyl-2,3-dihydro-lH-l ,4- benzodiazepin-3-yl)-2,3-bis(3,3,3-trifluoropropyl)succinamide (17), i.e. X=F, Y=H and Z=H; or (2R,3S)— N-((3S)-9-chloro-2-oxo-5-phenyl-2,3-dihydro-lH-l ,4-benzodiazepin-3-yl)-2,3-bis(3,3,3- trifluoropropyl)succinamide (18), i.e. X=Cl, Y=H and Z=H.
[0027] In another embodiment, the compound of Formula (III) comprises: (2R,3S)— N-((3S)-2-oxo-
5-phenyl-2,3-dihydro-lFl-l,4-benzodiazepin-3-yl)-3-(4,4,4-trifluorobutyl)-2-(3,3,3- trifluoropropyl)succinamide (19);
19
Figure imgf000013_0002
[0028] In another embodiment, the compound of Formula (III) comprises: (2R,3S)— N-((3S)-8- methoxy-2-oxo-5-phenyl-2, 3-dihydro- 1H-1 ,4-benzodiazepin-3-yl)-3-(4,4,4-trifLuorobutyl)-2-(3,3,3- trifluoropropyl)succinamide (20) 20
Figure imgf000014_0001
[0029] In another embodiment, the compound of Formula (III) comprises: (2R,3S)— N-((3S)-9-((2- methoxyethyl)amino)-2-oxo-5-phenyl-2,3-dihydro-lH-l,4-benzodiazepin-3-yl)-2,3-bis(3,3,3- triflu oropropyl)succinamide (21)
21
Figure imgf000014_0002
[0030] In another embodiment, the present invention provides compositions comprising compounds represented by the structure of Formula (I):
Figure imgf000014_0003
and/or at least one salt thereof, wherein:
Ri is -CH2CF3;
R2 is -CH2CH2CF3, or -CH2CH2CH2CF3;
R3 is H, -CH3 or Rx;
R4 is H or Ry;
Rx
is: -CH20C(0)CH(CH3)NH2, -CH20C(0)CH(NH2)CH(CH3)2, -CH2OC(0)CH((CH(
Figure imgf000015_0001
Ry is: -SCH2CH(NH2)C(0)0H, -SCH2CH(NH2)C(0)0H3,
or -SCH2CH(NH2)C(0)0C(CH3)3;
Ring A is phenyl or pyridinyl;
each Ra is independently Cl, C1-3 alkyl, -CFhOFl, -CF3, cyclopropyl, -OCFh, and/or -O(cyclopropyl);
each Rb is independently F, Cl, -CFh, -CFhOFl, -CF3, cyclopropyl, and/or -OCF13; y is zero, 1 or 2; and
z is 1 or 2.
[0031] In another embodiment, Ring A is phenyl; and R3 is H. In another embodiment, R2 is -CH2CH2CF3; and Ring A is phenyl. In another embodiment, R2 is -CH2CH2CF3; Ring A is phenyl; Ra is Ci-3 alkyl or -CF120F1; each Rb is independently F and/or Cl; and y is 1.
[0032] In another embodiment, the present invention provides compositions comprising compounds represented by the structure of Formula (IV) :
Figure imgf000015_0002
[0033] In another embodiment, the present invention provides compositions comprising compounds represented by the structure of Formula (V):
Figure imgf000015_0003
wherein R3 is H or Rx.
[0034] In another embodiment, the present invention provides compositions comprising (2R,3S)-N- ((3S)-5-(3-fluorophenyl)-9-methyl-2-oxo-2,3-dihydro-lH-l,4-benzodiazepin-3-yl)-2,3-bis(3,3,3- trifluoropropyl)succinamide (22); (2R,3S)-N-((3S)-5-(3-chlorophenyl)-9-ethyl-2-oxo-2,3-dihydro- lH-l,4-benzodiazepin-3-yl)-2,3-bis(3,3,3-trifluoropropyl)succinamide (23); (2R,3S)-N-((3S)-5-(3- chlorophenyl)-9-isopropyl-2 -oxo-2, 3-dihydro-lH-l, 4-benzodiazepin-3-yl)-2,3-bis(3, 3,3- trifluoropropyl)succinamide (24); (2R,3S)-N-(9-chloro-5-(3,4-dimethylphenyl)-2-oxo-2,3-dihydro- lH-l,4-benzodiazepin-3-yl)-3-(4,4,4-trifluorobutyl)-2-(3,3,3-trifluoropropyl)succinamide (25); (2R,3S)-N-(9-chloro-5-(3,5-dimethylphenyl)-2-oxo-2,3-dihydro-lH-l ,4-benzodiazepin-3-yl)-3- (4,4,4-trifluorobutyl)-2-(3,3,3-trifluoropropyl)succinamide (26); (2R,3S)-N-((3S)-9-ethyl-5-(3- methylphenyl)-2 -oxo-2, 3-dihydro-lH-l,4-benzodiazepin-3-yl)-2, 3-bis(3 ,3,3- trifluoropropyl)succinamide (27); (2R,3S)-N-((3S)-5-(3-chlorophenyl)-9-methyl-2-oxo-2,3-dihydro- lH-l,4-benzodiazepin-3-yl)-2,3-bis(3,3,3-trifluoropropyl)succinamide (28); (2R,3S)-N-((3S)-5-(3- chlorophenyl)-9-methyl-2-oxo-2,3-dihydro-lH-l,4-benzodiazepin-3-yl)-3-(4,4,4-trifluorobutyl)-2- (3,3,3-trifluoropropyl)succinamide (29); (2R,3S)-N-((3S)-5-(3-methylphenyl)-2-oxo-9-
(trifluoromethyl)-2,3-dihydro-lH-l,4-benzodiazepin-3-yl)-2,3-bis(3,3,3- trifluoropropyl)succinamide (30); (2R,3S)-N-((3S)-9-chloro-5-(3,5-dimethylphenyl)-2-oxo-2,3- dihydro-lH-l,4-benzodiazepin-3-yl)-2,3-bis(3,3,3-trifluoropropyl)succinamide (31); (2R,3S)-N-
((3S)-5-(3-methylphenyl)-2-oxo-9-(trifluoromethyl)-2,3-dihydro-lH-l,4-benzodiazepin-3-yl)-3- (4,4,4-trifluorobutyl)-2-(3,3,3-trifluoropropyl)succinamide (32); (2R,3S)-N-((3S)-9-isopropyl-5-(3- methylphenyl)-2 -oxo-2, 3-dihydro-lH-l,4-benzodiazepin-3-yl)-2, 3-bis(3 ,3,3- trifluoropropyl)succinamide (33); (2R,3S)-N-((3S)-9-(cyclopropyloxy)-5-(3-methylphenyl)-2-oxo- 2 ,3 -dihydro- 1 H- 1 ,4-benzodiazepin-3-yl)-3 -(4,4,4-trifluorobutyl)-2-(3 ,3,3- triflu oroprop yl) succinamide (34); (2R,3S)-N-((3S)-9-(cyclopropyloxy)-5-(3-methylphenyl)-2-oxo- 2 ,3 -dihydro- 1 H- 1 ,4-benzodiazepin-3-yl)-2 ,3-bis(3 ,3 ,3-trifluoropropyl)succinamide (35) ; (2R,3S)-N- ((3S)-9-chloro-5-(3-methylphenyl)-2 -oxo-2, 3-dihydro-lH-l,4-benzodiazepin-3-yl)-3-(4 ,4 ,4- triflu orobutyl)-2-(3, 3, 3 -triflu oropropyl) succinamide (36); (2R,3S)-N-((3S)-9-methyl-2-oxo-5-(3- (trifluoromethyl)phenyl)-2,3-dihydro-lH-l,4-benzodiazepin-3-yl)-3-(4,4,4-trifluorobutyl)-2-(3,3,3- trifluoropropyl) succinamide (37); (2R,3S)-N-((3S)-9-methyl-2-oxo-5-(3-(trifluoromethyl) phenyl)- 2,3-dihydro-lH-l,4-benzodiazepin-3-yl)-2,3-bis(3,3,3-trifluoropropyl) succinamide (38); (2R,3S)- N-((3S)-9-chloro-5-(2-methylphenyl)-2-oxo-2,3-dihydro-lH-l,4-benzodiazepin-3-yl)-2,3-bis(3,3,3- trifluoropropyl)succinamide (39); (2R,3S)-N-((3S)-5-(4-fluorophenyl)-9-methyl-2-oxo-2,3-dihydro- lH-l,4-benzodiazepin-3-yl)-2,3-bis(3,3,3-trifluoropropyl)succinamide (40); (2R,3S)-N-((3S)-9- chloro-5-(3-cyclopropylphenyl)-2-oxo-2,3 -dihydro- 1H- 1 ,4-benzodiazepin-3 -yl)-2 ,3 -bis(3,3,3- trifluoropropyl)succinamide (41); (2R,3S)-N-((3S)-5-(3-chlorophenyl)-9-methoxy-2-oxo-2,3- dihydro- 1 H- 1 ,4-bcnzodiazcpin-3-yl)-2,3-bis(3,3,3-trifluoiOpropyl)succinamidc (42); (2R,3S)-N-
((3S)-5-(4-chlorophenyl)-9-methoxy-2-oxo-2,3-dihydro-lH-l,4-benzodiazepin-3-yl)-2,3-bis(3,3,3- trifluoropropyl)succinamide (43); (2R,3S)-N-((3S)-9-chloro-5-(3-methylphenyl)-2-oxo-2,3-dihydro- 1 H- l ,4-benzodiazcpm-3-yl)-2,3-bis(3,3,3-tn†luoiopiOpyl)succ inamide (44); (2R,3S)-N-((3S)-5-(3- methylphenyl)-9-methoxy-2-oxo-2,3-dihydro-lH-l,4-benzodiazepin-3-yl)-2,3-bis(3,3,3- trifluoropropyl)succinamide (45); (2R,3S)-N-((3S)-5-(4-(hydroxymethyl)phenyl)-2-oxo-2,3- dihydro- 1 H- 1 ,4-bcnzodiazcpin-3-yl)-2,3-bis(3,3,3-trifluoiOpropyl)succinamidc (46); (2R,3S)-N-
((3S)-5-(2-methylphenyl)-2-oxo-2,3-dihydro-lH-l,4-benzodiazepin-3-yl)-2,3-bis(3,3,3- trifluoropropyl)succinamide (47); (2R,3S)-N-((3S)-5-(3-methylphenyl)-2-oxo-2,3-dihydro-lH-l ,4- bcnzod iazcpin-3-yl)-2, 3-bis(3, 3, 3-tri†luoiopropyl)su coin amide (48); (2R,3S)-N-((3S)-9-methoxy-2- oxo-5-(5-(tri†luoiomcthyl)-2-pyi idinyl )-2,3-dihydro- 1 H- 1 ,4-bcnzodiazcpin-3-yl)-2,3-bis(3,3,3- trifluoropropyl)sueeinamide (49); (2R,3S)-N-((3S)-5-(5-chloro-2-pyridinyl)-9-methoxy-2-oxo-2,3- dihydro- 1 H- 1 ,4-bcnzodiazcpin-3-yl)-2,3-bis(3,3,3-ti i†luoropropyl)succinamidc (50); (2R,3S)-N-
((3S)-5-(4-methoxyphenyl)-2-oxo-2,3-dihydro-lH-l,4-benzodiazepin-3-yl)-2,3-bis(3,3,3- trifluoropropyl)succinamide (51); (2R,3S)-N-((3S)-5-(4-methylphenyl)-2-oxo-2,3-dihydro-lH-l ,4- benzodiazepin-3-yl)-2,3-bis(3,3,3-trifluoropropyl)succinamide (52); (2R,3S)-N-((3S)-5-(3- fluorophenyl)-9-(hydroxymethyl)-2-oxo-2 ,3 -dihydro- 1H- 1 ,4-benzodiazepin-3-yl)-2 ,3 -bis(3 ,3 ,3- trifluoropropyl)succinamide (53); ((3S)-3-(((2R,3S)-3-carbamoyl-6,6,6-ti i†luoro-2-(3,3,3- trifluoropropyl)hexanoyl)amino)-5-(3-fluorophenyl)-9-methyl-2-oxo-2,3-dihydro-lH-l,4- benzodiazepin-l-yl)methyl L-valinate (54); ((3S)-3-(((2R,3S)-3-carbamoyl-6,6,6-ti i†luoro-2-(3,3,3- trifluoropropyl)hexanoyl)amino)-5-(3-fluorophenyl)-9-methyl-2-oxo-2,3-dihydro-lH-l,4- benzodiazepin-l-yl)methyl L-alaninate (55); S-(((2S,3R)-6,6,6-trifluoro-3-(((3S)-5-(3- fluorophenyl)-9-methyl-2-oxo-2, 3-dihydro- 1H- 1 ,4-benzodiazepin-3-yl)carbamoyl)-2-(3 ,3 ,3- trifluoropropyl)hexanoyl)amino)-L-cysteine (56); tert- butyl S-(((2S,3R)-6,6,6-trrfluoro-3-(((3S)-5-
(3-fluorophenyl)-9-methyl-2-oxo-2,3-dihydro-lH-l,4-benzodiazepin-3-yl)carbamoyl)-2-(3,3,3- trifluoropropyl)hexanoyl)amino)-L-eysteinate (57); methyl S-(((2S,3R)-6,6,6-trrfluoro-3-(((3S)-5-
(3-fluorophenyl)-9-methyl-2-oxo-2,3-dihydro-lH-l,4-benzodiazepin-3-yl)carbamoyl)-2-(3,3,3- trifluoropropyl) hexanoyl)amino)-L-cysteinate (58); ((3S)-3-(((2R,3S)-3-carbamoyl-6,6,6-trifluoro- 2-(3,3,3-trifluoropropyl)hexanoyl)amino)-5-(3-fluorophenyl)-9-methyl-2-oxo-2,3-dihydro-lH-l,4- benzodiazepin-l-yl)methyl (4-(phosphonooxy)phenyl)acetate (59); and ((3S)-3-(((2R,3S)-3- carbamoyl-6,6,6-trifluoro-2-(3,3,3-trifluoropropyl)hexanoyl)amino)-5-(3-fluorophenyl)-9-methyl-2- oxo-2, 3-dihydro-lH-l,4-benzodiazepin-l-yl)methyl L-valyl-L-valinate (60); and salts thereof.
[0035] In another embodiment, the present invention provides compositions comprising compounds represented by the structure of Formula (I):
Figure imgf000018_0001
and/or at least one salt thereof, wherein:
Ri is -CH2CF3 or -CH2CH2CF3;
R2 is -CH2CF3, -CH2CH2CF3, or -CH2CH2CH2CF3;
R3 is H, -CH3 or Rx;
R4 is Fl or Ry;
Rx
is: -CH20C(0)CH(CH3)NH2, -
CH3)2)NHC(0)CH(NH2)CH(C
Figure imgf000018_0002
H3C
-CH20C(0)CH2C(CH3)2 // w CH
-CH2OC(0)
(HO)2(0)PO , or A w CH2OP(0)(OH)2
Ry is: -SCH2CH(NH2)C(0)0H, -SCH2CH(NH2)C(0)0H3,
or -SCH2CH(NH2)C(0)0C(CH3)3;
Ring A is phenyl or pyridinyl;
each Ra is independently F, Cl, -CN, -OCH3, C1-3 alkyl, -CH2OH, -CF3,
cyclopropyl, -OCH3, -O(cyclopropyl) and/or -NHCH2CH2OCH3;
each Rb is independently F, Cl, -CH3, -CH2OH, -CF3, cyclopropyl, and/or -OCH3; y is zero, 1 or 2; and
z is zero, 1, or 2
provided that if Ring A is phenyl, z is zero, and y is 1 or 2 then at least one Ra is Ci-3 alkyl, -CH2OH, -CF3, cyclopropyl, or -O(cyclopropyl);
provided that if R3 is Rx then R4 is H; and provided that if R4 is Ry then R3 is H or -CH3.
[0036] In another embodiment, a structure as described hereinabove comprises one or more of the following provisos: provided that if Ring A is phenyl, z is zero, and y is 1 or 2 then at least one Ra is Ci-3 alkyl, -CH2OH, -CF3, cyclopropyl, or -O(cyclopropyl); provided that if R3 is Rx then R4 is H; and provided that if R4 is Ry then R3 is H or -CH3.
[0037] In another embodiment, the present invention provides compositions comprising compounds represented by the following structure:
Figure imgf000019_0001
[0038] In another embodiment, the compounds as described herein comprise prodrugs of one or more of the compounds.
[0039] U.S. Patent No. 9,273,014, which is incorporated herein in its entirety, discloses various compounds of Formula (I):
Figure imgf000019_0002
and/or at least one salt thereof, wherein:
Ri is -CH2CH2CF3;
R2 is -CH2CH2CF3 or -CH2CH2CH2CF3;
R3 is H, -CH3, or Rx;
R4 is Fl or Ry;
Rx
is: -CH20C(0)CH(CH3)NH2, -CH20C(0)CH(NH2)CH(CH3)2, -CH20C(0)CH((CH(CH3
Figure imgf000020_0001
Ry is: -SCH2CH(NH2)C(0)0H, -SCH2CH(NH2)C(0)0CH3,
or -SCH2CH(NH2)C(0)0C(CH3)3;
Ring A is phenyl or pyridinyl;
each Ra is independently Cl, Ci-3 alkyl, -CH2OH, -CF3, cyclopropyl, -OCH3,
and/or -O(cyclopropyl);
each Rb is independently F, Cl, -CF13, -CFl2OF[, -CF3, cyclopropyl, and/or -OCFl3;
y is zero, 1 , or 2; and
z is 1 or 2.
[0040] U.S. Patent No. 9,273,014 also discloses the compound of Formula (22):
Figure imgf000020_0002
which, in one embodiment, has the chemical name (2R,3S)-N-((3S)-5-(3-fluorophenyl)-9-methyl-2- oxo-2,3-dihydro-lFl-l,4-benzodiazepin-3-yl)-2,3-bis(3,3,3-trifluoropropyl)succinamide. U.S. Patent No. 9,273,014 also discloses a process for synthesizing the compounds as well as other compounds of Formula (I), which are to be considered as part of the present invention.
[0041] U.S. Patent No. 8,629,136, which is incorporated by reference herein in its entirety, discloses compounds of Formula (III):
Figure imgf000021_0001
and/or at least one salt thereof, wherein:
R3 is H or -CH3; and
each Ra is independently F, Cl, -CN, -OCH3 and/or -NHCH2CH2OCH3.
U.S. Patent No. 8,629,136 also discloses the compound of Formula (1):
Figure imgf000021_0002
which, in one embodiment, has the chemical name (2R,3S)— N-((3S)-l-methyl-2-oxo-5-phenyl-2,3- dihydro-lFl-l,4-benzodiazepin-3-yl)-2,3-bis(3,3,3-trifluoropropyl)succinamide. In one embodiment, the compounds are Notch inhibitors. U.S. Patent No. 8,629,136 discloses a process for synthesizing the compounds as well as other compounds of Formula (I), which are to be considered as part of the present invention.
[0042] In one embodiment, the present invention provides compositions comprising compounds as described herein formulated at a dose of 4 mg. In one embodiment, the present invention provides compositions comprising compounds as described herein formulated for intravenous administration.
[0043] The present invention may be embodied in other specific forms without departing from the spirit or essential attributes thereof. This invention encompasses all combinations of the aspects and/or embodiments of the invention noted herein. It is understood that any and all embodiments of the present invention may be taken in conjunction with any other embodiment or embodiments to describe addition more embodiments. It is also to be understood that each individual element of the embodiments is meant to be combined with any and all other elements from any embodiment to describe an additional embodiment.
Combined Treatments
[0044] In one embodiment, compositions of the present invention or for use in the methods of the present invention comprise one or more cancer therapeutic agents in combination with one or more bisfluoroalkyl-l,4-benzodiazepinone compounds described hereinabove. In one embodiment, the cancer therapeutic agent comprises an anti-CD20 agent.
[0045] In another embodiment, the present invention provides a composition comprising one or more compounds represented by the structure of Formula (I) and an anti-CD20 agent as described herein in combination with an immunotherapeutic. In one embodiment, the immunotherapeutic comprises a monoclonal antibody.
[0046] In another embodiment, the monoclonal antibody comprises an anti-CD20 antibody. Anti- CD20 antibodies can bind to CD20 and mediate antibody dependent cell death and complement cell death, by natural killer (NK) cells, thus eliminating malignant B-cells. In one embodiment, the anti- CD20 antibody comprises rituximab. In another embodiment, the anti-CD20 antibody comprises a rituximab biosimilar, or any next generation anti-CD20. In another embodiment, the anti-CD20 antibody comprises any other anti-CD20 antibody suitable for use in accordance with the compositions and methods described herein, including, without limitation, ocrelizumab, Ocaratuzumab (including AME-D, AME-l33v, LY2469298) veltuzumab (including subcutaneous, ha20, IMMU-106, intravenous), obinutuzumab (including GA101 ; Gazyva, Gazyvaro, RO5072759, RG7159), ofatumumab (including Arzerra OMB157, humax-cd20, 2F2), tositumomab (including Bexxar), ibritumomab (including Zevalin, ibritumamab tiuxetan (IDEC-Y2B8)), Prol 31921 (RhuMAb; vl l4), TRU-015, Ublituximab (including LFB-R603, EMAB-6, TG-1101/TG1202, TGTX-1101 (LFB SA)), DI-Leul6-IL2, FBTA05, TPBs05, CAR-T CD20 (CBM-C20.1, CBM- CD20.1), chimeric anti-CD20 mAb (SCT400), IGN002, MT-3724, REGN1979, RG6026, ATTCK20 (ACTR087), XmAbl3676, EP-400, FB811, IMM03, 20-(74)-(74), CD20 mAb, (Inno vent Biologies), KN001, rituximab and its biosimilars (including Mab Thera, Rituxan, R105, RG105, IDEC-C2B8, Zytux, AcellBia, BCD-020, Blitzima, Ritemvia, TRuxima, Tuxella, CT-P10, Reditux, Rixathon, Rituxan Flycela (subcutaneous mabthera, subcutaneous rituximab, Mabthera SC, ABP798, IBI301, RTXM83, PF-05280586, HLX01, TL011, AP056, TG20, ) or a combination thereof.
[0047] In another embodiment, the present invention provides methods that include administering a composition comprising one or more compounds represented by the structure of Formula (I) as described herein in combination with an anti-CD20 therapy. In another embodiment, in addition to those described elsewhere herein, the anti-CD20 therapy comprises any other anti-CD20 therapy suitable for use in accordance with the compositions and methods described herein, including, without limitation, CAR-T therapy, bispecific antibodies, T cell engagers, antibody drug conjugates, or a combination thereof.
[0048] In one embodiment, an anti-CD20 agent as described herein comprises a CD20 modulatory compound or reagent. In one embodiment, the CD20 modulatory compound or reagent comprises Bryostatin-1, Interleukin-4, GMCSF, Tumor necrosis factor-a, one or more Statins, Interferon-a, L- 744,832, Bortezomib, 5-azacytidine, Trichostatin-A, Valproic acid (VPA) or Romidepsin, or a combination thereof. In another embodiment, radiation treatment modulates CD20.
[0049] In one embodiment, the anti-CD20 agent comprises an anti-CD20 antibody. In one embodiment, the anti-CD20 antibody comprises an anti-CD20 monoclonal antibody.
[0050] In another embodiment, compositions of the present invention or for use in the methods of the present invention comprise one or more compounds represented by the structure of Formula (I) as described herein in combination with rituximab.
[0051] In one embodiment, compositions of the present invention or for use in the methods of the present invention comprise one or more additional cancer therapeutic agents in combination with one or more bisfluoroalkyl-l ,4-benzodiazepinone compounds and one or more anti-CD20 agent.
[0052] In treating cancer, a combination of chemotherapeutic agents and/or other treatments (e.g., radiation therapy) is often advantageous. An additional agent may have the same or different mechanism of action than the primary therapeutic agents. For example, drug combinations may be employed wherein the two or more drugs being administered act in different manners or in different phases of the cell cycle, and/or where the two or more drugs have nonoverlapping toxicities or side effects, and/or where the drugs being combined each has a demonstrated efficacy in treating the particular disease state manifested by the patient.
[0053] In one embodiment, a method is provided for treating cancer comprising administering to a mammal in need thereof a composition as described herein and administering one or more additional anti-cancer agents.
[0054] In one embodiment, the phrase“additional anti-cancer agent” refers to a drug selected from any one or more of the following: alkylating agents (including nitrogen mustards, methanesulphonate, busulphan, alkyl sulfonates, nitrosoureas, ethylenimine derivatives, and triazenes, or a combination thereof); anti-angiogenics (including matrix metalloproteinase inhibitors); antimetabolites (including adenosine deaminase inhibitors, folic acid antagonists, purine analogues, and pyrimidine analogues); antibiotics or antibodies (including monoclonal antibodies, CTLA-4 antibodies, anthracyclines); aromata.se inhibitors; cell-cycle response modifiers; enzymes; farnesyl-protein transferase inhibitors; hormonal and antihormonal agents and steroids (including synthetic analogs, glucocorticoids, estrogens/anti-estrogens [e.g., SERMs], androgens/anti-androgens, progestins, progesterone receptor agonists, and luteinizing hormone-releasing [LHRH] agonists and antagonists); insulin-like growth factor (IGF)/insulin-like growth factor receptor (IGFR) system modulators (including IGFR1 inhibitors); integrin- signaling inhibitors; kinase inhibitors (including multi-kinase inhibitors and/or inhibitors of Src kinase or Src/abl, cyclin dependent kinase [CDK] inhibitors, panHer, Her-l and Her-2 antibodies, VEGF inhibitors, including anti-VEGF antibodies, EGFR inhibitors, PARP (poly ADP-ribose polymerase) inhibitors, mitogen- activated protein [MAP] inhibitors, MET inhibitors, MEK inhibitors, Aurora kinase inhibitors, PDGF inhibitors, and other tyrosine kinase inhibitors or serine/threonine kinase inhibitors; microtubule-disruptor agents, such as ecteinascidins or their analogs and derivatives; microtubule-stabilizing agents such as taxanes, platinum-based antineoplastic drugs (platins) such as cisplatin, carboplatin, oxaliplatin, nedaplatin, triplatin tetranitrate, phenanthriplatin, picoplatin and satraplatin, and the naturally-occurring epothilones and their synthetic and semi-synthetic analogs; microtubule-binding, destabilizing agents (including vinca alkaloids); topoisomerase inhibitors; prenyl-protein transferase inhibitors; platinum coordination complexes; signal transduction inhibitors; and other agents used as anti-cancer and cytotoxic agents such as biological response modifiers, growth factors, and immune modulators.
[0055] In another embodiment, the present invention provides a composition comprising one or more compounds represented by the structure of Formula (I) and an anti-CD20 agent as described herein in combination with an inhibitor of mammalian target of rapamycin (mTOR). In one embodiment, the mTOR inhibitor comprises Everolimus. In another embodiment, the mTOR inhibitor comprises sirolimus (rapamycin). In another embodiment, the mTOR inhibitor comprises temsirolimus.
[0056] In another embodiment, the mTOR inhibitor comprises a dual mammalian target of rapamycin/phosphoinositide 3-kinase inhibitor, which in one embodiment, comprises NVP-BEZ235 (dactolisib), GSK2126458, XL765, or a combination thereof.
[0057] In another embodiment, the mTOR inhibitor comprises a second generation mTOR inhibitor, which, in one embodiment, comprises AZD8055, INK128/MLN0128, OSI027, or a combination thereof.
[0058] In another embodiment, the mTOR inhibitor comprises a third generation mTOR inhibitor, which, in one embodiment, comprises RapaLinks.
[0059] In another embodiment, the present invention provides a composition comprising one or more compounds represented by the structure of Formula (I) and an anti-CD20 agent as described herein in combination with an mTOR inhibitor and a chemotherapeutic drug. In one embodiment, the mTOR inhibitor comprises everolimus. In one embodiment, the chemotherapeutic drug comprises cisplatin.
[0060] In another embodiment, the present invention provides a composition comprising one or more compounds represented by the structure of Formula (I) and an anti-CD20 agent as described herein in combination with bisphosphonates.
[0061 ] In another embodiment, the present invention provides a composition comprising one or more compounds represented by the structure of Formula (I) and an anti-CD20 agent as described herein in combination with cancer growth blockers.
[0062] In another embodiment, the present invention provides a composition comprising one or more compounds represented by the structure of Formula (I) and an anti-CD20 agent as described herein in combination with proteasome inhibitors.
[0063] In another embodiment, the present invention provides a composition comprising one or more compounds represented by the structure of Formula (I) and an anti-CD20 agent as described herein in combination with one or more interferons.
[0064] In another embodiment, the present invention provides a composition comprising one or more compounds represented by the structure of Formula (I) and an anti-CD20 agent as described herein in combination with one or more interleukins.
[0065] In another embodiment, the present invention provides a composition comprising one or more compounds represented by the structure of Formula (I) and an anti-CD20 agent as described herein in combination with an alkylating drug. In one embodiment, the alkylating drug comprises Procarbazine (Matulane), Dacarbazine (DTIC), Altretamine (Flexalen), or a combination thereof.
[0066] In another embodiment, the present invention provides a composition comprising one or more compounds represented by the structure of Formula (I) and an anti-CD20 agent as described herein in combination with an antimetabolite. In one embodiment, the antimetabolite comprises an antifolic acid compound (Methotrexate), an amino acid antagonists (Azaserine), or a combination thereof.
[0067] In another embodiment, the present invention provides a composition comprising one or more compounds represented by the structure of Formula (I) and an anti-CD20 agent as described herein in combination with a purine antagonist. In one embodiment, the purine antagonist comprises Mercaptopurine (6-MP), Thioguanine (6-TG), Fludarabine Phosphate, Cladribine (Leustatin), Pentostatin (Nipent), or a combination thereof.
[0068] In another embodiment, the present invention provides a composition comprising one or more compounds represented by the structure of Formula (I) and an anti-CD20 agent as described herein in combination with a pyrimidine antagonist. In one embodiment, the pyrimidine antagonist comprises Fluorouracil (5-FU), Cytarabine (ARA-C), Azacitidine, or a combination thereof.
[0069] In another embodiment, the present invention provides a composition comprising one or more compounds represented by the structure of Formula (I) and an anti-CD20 agent as described herein in combination with a plant alkaloid. In one embodiment, the pyrimidine antagonist comprises Vinblastine (Velban), Vincristine (Oncovin), Etoposide (VP-16, VePe-sid), Teniposide (Vumon), Topotecan (Hycamtin), Irinotecan (Camptosar), Paclitaxel (Taxol), Docetaxel (Taxotere), or a combination thereof.
[0070] In another embodiment, the present invention provides a composition comprising one or more compounds represented by the structure of Formula (I) and an anti-CD20 agent as described herein in combination with FOLFIRI, wherein in one embodiment FOLFIRI comprises folinic acid (leucovorin), fluorouracil (5-FU) and irinotecan (Camptosar). In another embodiment, the present invention provides a composition comprising one or more compounds represented by the structure of Formula (I) and an anti-CD20 agent as described herein in combination with folinic acid (leucovorin), fluorouracil (5-FU), irinotecan (Camptosar), or a combination thereof.
[0071] In another embodiment, the present invention provides a composition comprising one or more compounds represented by the structure of Formula (I) and an anti-CD20 agent as described herein in combination with an antibiotic. In one embodiment, the antibiotic comprises Anthracyclines, Doxorubicin (Adriamycin, Rubex, Doxil), Daunorubicin (DaunoXome), Dactinomycin (Cosmegen), Idarubincin (Idamycin), Plicamycin (Mithramycin), Mitomycin (Mutamycin), Bleomycin (Blenoxane), or a combination thereof.
[0072] In another embodiment, the present invention provides a composition comprising one or more compounds represented by the structure of Formula (I) and an anti-CD20 agent as described herein in combination with an immunotherapeutic. In one embodiment, the immunotherapeutic comprises a monoclonal antibody. In one embodiment, the monoclonal antibody comprises an anti-PD-1 antibody, which in one embodiment comprises nivolumab.
[0073] In another embodiment, the monoclonal antibody comprises alemtuzumab (Campath®), trastuzumab (Herceptin®), Bevacizumab (Avastin®), Cetuximab (Erbitux®), or a combination thereof. In another embodiment, the monocolonal antibody comprises a radiolabeled antibody, which, in one embodiment, comprises britumomab, tiuxetan (Zevalin®), or a combination thereof. In another embodiment, the monocolonal antibody comprises a chemolabeied antibody, which in one embodiment comprises Brentuximab vedotin (Adcetris®), Ado-trastuzumab emtansine (Kadcyla®, also called TDM-1), denileukin diftitox (Ontak®), or a combination thereof In another embodiment, the monocolonal antibody comprises a bispecific antibody, which in one embodiment, comprises blinatumomab (Blincyto).
[0074] In another embodiment, the present invention provides a composition comprising one or more compounds represented by the structure of Formula (I) and an anti-CD20 agent as described herein in combination with a hormonal agent. In one embodiment, the hormonal agent comprises Tamoxifen (Nolvadex), Flutamide (Eulexin), Gonadotropin-Releasing Flormone Agonists, (Leuprolide and Goserelin (Zoladex)), Aromatase Inhibitors, Aminoglutethimide, Anastrozole (Arimidex), or a combination thereof.
[0075] In another embodiment, the present invention provides a composition comprising one or more compounds represented by the structure of Formula (I) and an anti-CD20 agent as described herein in combination with Amsacrine, Hydroxyurea (Hydrea), Asparaginase (El-spar), Mitoxantrone (Novantrone), Mitotane, Retinoic Acid Derivatives, Bone Marrow Growth Factors, Amifostine, or a combination thereof.
[0076] In another embodiment, the present invention provides a composition comprising one or more compounds represented by the structure of Formula (I) and an anti-CD20 agent as described herein in combination with an agent that inhibits one or more cancer stem cell pathways. In one embodiment, such agent comprises an inhibitor of Hedgehog, WNT, BMP, or a combination thereof.
[0077] In another embodiment, the present invention provides a composition comprising one or more compounds represented by the structure of Formula (I) and an anti-CD20 agent as described herein in combination with any one or more of the following: Revlimid, Avastin, Herceptin, Rituxan, Opdivo, Gleevec, Imbruvica, Velcade, Zytiga, Xtandi, Alimta, Gadasil, Ibrance, Perjeta, Tasigna, Xgeva, Afinitor, Jakafi, Tarceva, Keytruda, Sutent, Yervoy, Nexavar, Zoladex, Erbitux, Dazalex, Xeloda, Gazyva, Venclexta, and Tecentriq.
[0078] In another embodiment, the present invention provides a composition comprising one or more compounds represented by the structure of Formula (I) and an anti-CD20 agent as described herein in combination with any one or more of the following: abemaciclib, epacadostat, apalutamide, Carfilzomib, Crizotinib (PF-02341066), GDC-0449 (vismodegib), OncoVex, PLX4032 (RG7204), Ponatinib, SGN-35 (brentuximab vedotin), Tivozanib (AV-951), T-DM1 (Trastuzumab-DMl), and XL184 (cabozantinib).
[0079] Accordingly, the compositions of the present invention may be administered in combination with other anti-cancer treatments useful in the treatment of cancer or other proliferative diseases. The invention herein further comprises use of the compositions of the present invention in preparing medicaments for the treatment of cancer, and/or it comprises the packaging of the compositions of the present invention together with instructions that the compositions be used in combination with other anti-cancer or cytotoxic agents and treatments for the treatment of cancer.
[0080] The compounds of the present invention can be formulated or co-administered with other therapeutic agents that are selected for their particular usefulness in addressing side effects associated with the aforementioned conditions. For example, compounds of the invention may be formulated with agents to prevent nausea, hypersensitivity and gastric irritation, such as antiemetics, and Hi and ih antihistaminics.
[0081] In one embodiment, pharmaceutical compositions are provided comprising a compound of Formula (I) or prodrug thereof; one or more additional agents selected from a kinase inhibitory agent (small molecule, polypeptide, and antibody), an immunosuppressant, an anti-cancer agent, an anti viral agent, anti-inflammatory agent, antifungal agent, antibiotic, or an anti-vascular hyperproliferation compound; and any pharmaceutically acceptable carrier, adjuvant or vehicle.
[0082] The above other therapeutic agents, when employed in combination with the compounds of the present invention, may be used, for example, in those amounts indicated in the Physicians' Desk Reference (PDR) or as otherwise determined by one of ordinary skill in the art. In the methods of the present invention, such other therapeutic agent(s) may be administered prior to, simultaneously with, or following the administration of the inventive compounds.
Pharmaceutical Compositions
Formulations
[0083] Also embraced within this invention is a class of pharmaceutical compositions comprising the compound of Formula (I) and one or more non-toxic, pharmaceutically- acceptable carriers and/or diluents and/or adjuvants (collectively referred to herein as“carrier” materials) and, if desired, other active ingredients.
[0084] The compounds of Formula (I) may be administered by any suitable route, preferably in the form of a pharmaceutical composition adapted to such a route, and in a dose effective for the treatment intended. The compounds and compositions of the present invention may, for example, be administered in dosage unit formulations containing conventional pharmaceutically or food grade acceptable carriers, adjuvants, and vehicles. For example, the pharmaceutical carrier may contain a mixture of mannitol or lactose and microcrystalline cellulose. The mixture may contain additional components such as a lubricating agent, e.g., magnesium stearate and a disintegrating agent such as crospovidone. The carrier mixture may be filled into a gelatin capsule or compressed as a tablet. The pharmaceutical composition may be administered as an oral dosage form or an infusion, for example. [0085] For oral administration, the pharmaceutical composition may be in the form of, for example, a tablet, capsule, liquid capsule, suspension, or liquid. The pharmaceutical composition is preferably made in the form of a dosage unit containing a particular amount of the active ingredient. For example, the pharmaceutical composition may be provided as a tablet or capsule comprising an amount of active ingredient in the range of from about 0.3 to 2000 mg, preferably from about 0.3 to 500 mg, and more preferably from about 5 to 150 mg. A suitable daily dose for a human or other mammal may vary widely depending on the condition of the patient and other factors, but, can be determined using routine methods. Moreover, if a particular dose is higher than desired or tolerated in a daily dosing regimen, dosing can be modified to achieve desired results by utilizing a modified appropriate dosing schedule, such as, for example, twice a week dosing or other suitable schedule. Such modifications and variations are within the scope and knowledge of the ordinarily skilled artisan.
[0086] Any pharmaceutical composition contemplated herein can, for example, be delivered orally via any acceptable and suitable oral preparations. Exemplary oral preparations, include, but are not limited to, for example, tablets, troches, lozenges, pills, aqueous and oily suspensions, dispersible powders, pellets or granules, emulsions, hard and soft capsules, liquid capsules, syrups, and elixirs. Pharmaceutical compositions intended for oral administration can be prepared according to any methods known in the art for manufacturing pharmaceutical compositions intended for oral administration. Tablet and other oral preparations also can include, without limitation, buccal, chewable, effervescent, modified release, orally disintegrating, sublingual, for oral solution, for oral suspension, triturates, or any other forms suitable for use in accordance with the compositions and methods described herein. In order to provide pharmaceutically palatable preparations, a pharmaceutical composition in accordance with the invention can contain at least one agent selected from sweetening agents, flavoring agents, coloring agents, demulcents, antioxidants, and preserving agents.
[0087] A tablet can, for example, be prepared by admixing at least one compound of Formula (I) with at least one non-toxic pharmaceutically acceptable excipient suitable for the manufacture of tablets. Exemplary excipients include, but are not limited to, for example, inert diluents, such as, for example, calcium carbonate, sodium carbonate, lactose, calcium phosphate, and sodium phosphate; granulating and disintegrating agents, such as, for example, microcrystalline cellulose, sodium croscarmellose, com starch, and alginic acid; binding agents, such as, for example, starch, gelatin, polyvinyl-pyrrolidone, and acacia; and lubricating agents, such as, for example, magnesium stearate, stearic acid, and talc. Additionally, a tablet can either be uncoated, or coated or encapsulated by known techniques to either mask the bad taste of an unpleasant tasting drug, or delay disintegration and absorption of the active ingredient in the gastrointestinal tract thereby sustaining the effects of the active ingredient for a longer period. Exemplary water soluble taste masking materials, include, but are not limited to, hydroxypropyl-methylcellulose and hydroxypropyl-cellulose. Exemplary time delay materials, include, but are not limited to, ethyl cellulose, poly (meth) acrylate and cellulose acetate butyrate. Alternatively, if desired, a formulation can be prepared to include only drug substance.
[0088] Hard gelatin capsules can, for example, be prepared by mixing at least one compound of Formula (I) with at least one inert solid diluent, such as, for example, calcium carbonate; calcium phosphate; and kaolin. Alternatively, if desired, the capsule can be prepared to include only drug substance.
[0089] Soft gelatin capsules can, for example, be prepared by mixing at least one compound of Formula (I) with at least one water soluble carrier, such as, for example, polyethylene glycol; and at least one oil medium, such as, for example, peanut oil, liquid paraffin, and olive oil.
[0090] An aqueous suspension can be prepared, for example, by admixing at least one compound of Formula (I) with at least one excipient suitable for the manufacture of an aqueous suspension. Exemplary excipients suitable for the manufacture of an aqueous suspension, include, but are not limited to, for example, suspending agents, such as, for example, sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethyl-cellulose, sodium alginate, alginic acid, polyvinyl pyrrolidone, gum tragacanth, and gum acacia; dispersing or wetting agents, such as, for example, a naturally-occurring phosphatide, e.g., lecithin; condensation products of alkylene oxide with fatty acids, such as, for example, polyoxyethylene stearate; condensation products of ethylene oxide with long chain aliphatic alcohols, such as, for example heptadecaethylene-oxycetanol; condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol, such as, for example, polyoxyethylene sorbitol monooleate; and condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, such as, for example, polyethylene sorbitan monooleate. An aqueous suspension can also contain at least one preservative, such as, for example, ethyl and n-propyl p-hydroxybenzoate; at least one coloring agent; at least one flavoring agent; and/or at least one sweetening agent, including but not limited to, for example, sucrose, saccharin, and aspartame.
[0091] Oily suspensions can, for example, be prepared by suspending at least one compound of Formula (I) in either a vegetable oil, such as, for example, arachis oil; olive oil; sesame oil; and coconut oil; or in mineral oil, such as, for example, liquid paraffin. An oily suspension can also contain at least one thickening agent, such as, for example, beeswax; hard paraffin; and cetyl alcohol. In order to provide a palatable oily suspension, at least one of the sweetening agents already described hereinabove, and/or at least one flavoring agent can be added to the oily suspension. An oily suspension can further contain at least one preservative, including, but not limited to, for example, an antioxidant, such as, for example, butylated hydroxyanisol, and alpha-tocopherol.
[0092] Dispersible powders and granules can, for example, be prepared by admixing at least one compound of Formula (I) with at least one dispersing and/or wetting agent; at least one suspending agent; and/or at least one preservative. Suitable dispersing agents, wetting agents, and suspending agents are as already described above. Exemplary preservatives include, but are not limited to, for example, anti-oxidants, e.g., ascorbic acid. In addition, dispersible powders and granules can also contain at least one excipient, including, but not limited to, for example, sweetening agents; flavoring agents; and coloring agents.
[0093] An emulsion of at least one compound of Formula (I) can, for example, be prepared as an oil- in-water emulsion. The oily phase of the emulsions comprising compounds of Formula (I) may be constituted from known ingredients in a known manner. The oil phase can be provided by, but is not limited to, for example, a vegetable oil, such as, for example, olive oil and arachis oil; a mineral oil, such as, for example, liquid paraffin; and mixtures thereof. While the phase may comprise merely an emulsifier, it may comprise a mixture of at least one emulsifier with a fat or an oil or with both a fat and an oil. Suitable emulsifying agents include, but are not limited to, for example, naturally- occurring phosphatides, e.g., soy bean lecithin; esters or partial esters derived from fatty acids and hexitol anhydrides, such as, for example, sorbitan monooleate; and condensation products of partial esters with ethylene oxide, such as, for example, polyoxyethylene sorbitan monooleate. Preferably, a hydrophilic emulsifier is included together with a lipophilic emulsifier which acts as a stabilizer. It is also preferred to include both an oil and a fat. Together, the emulsifier(s) with or without stabilizer(s) make-up the so-called emulsifying wax, and the wax together with the oil and fat make up the so- called emulsifying ointment base which forms the oily dispersed phase of the cream formulations. An emulsion can also contain a sweetening agent, a flavoring agent, a preservative, and/or an antioxidant. Emulsifiers and emulsion stabilizers suitable for use in the formulation of the present invention include Tween 60, Span 80, cetostearyl alcohol, myristyl alcohol, glyceryl monostearate, sodium lauryl sulfate, glyceryl distearate alone or with a wax, or other materials well known in the art.
[0094] In another embodiment, the compounds of Formula (I) can be formulated as a nanoparticle, lipid nanoparticle, microparticle or liposome.
[0095] The compounds of Formula (I) can, for example, also be delivered intravenously, subcutaneously, and/or intramuscularly via any pharmaceutically acceptable and suitable injectable form. Exemplary injectable forms include, but are not limited to, for example, sterile aqueous solutions comprising acceptable vehicles and solvents, such as, for example, water, Ringer's solution, and isotonic sodium chloride solution; sterile oil-in-water microemulsions; and aqueous or oleaginous suspensions.
[0096] For example, the composition may be provided for intravenous administration comprising an amount of active ingredient in the range of from about 0.2 to 150 mg. In another embodiment, the active ingredient is present in the range of from about 0.3 to 10 mg. In another embodiment, the active ingredient is present in the range of from about 4 to 8.4 mg. In one embodiment, the active ingredient is administered at a dose of about 4 mg. In another embodiment, the active ingredient is administered at a dose of about 6 mg. In another embodiment, the active ingredient is administered at a dose of about 8.4 mg.
[0097] In another embodiment, the active ingredient is administered at a dose of about 0.3 mg. In another embodiment, the active ingredient is administered at a dose of about 0.6 mg. In another embodiment, the active ingredient is administered at a dose of about 1.2 mg. In another embodiment, the active ingredient is administered at a dose of about 2.4 mg.
[0098] Formulations for parenteral administration may be in the form of aqueous or non-aqueous isotonic sterile injection solutions or suspensions. These solutions and suspensions may be prepared from sterile powders or granules using one or more of the carriers or diluents mentioned for use in the formulations for oral administration or by using other suitable dispersing or wetting agents and suspending agents. The compounds may be dissolved in any suitable solvent, including, without limitation, water, polyethylene glycol, propylene glycol, ethanol, com oil, cottonseed oil, peanut oil, sesame oil, benzyl alcohol, sodium chloride, tragacanth gum, and/or various buffers. Other adjuvants and modes of administration are well and widely known in the pharmaceutical art. The active ingredient may also be administered by injection as a composition with suitable carriers including saline, dextrose, or water, or with cyclodextrin (i.e., CAPTISOF®), cosolvent solubilization (i.e., propylene glycol) or micellar solubilization (i.e., Tween 80).
[0099] The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, for example as a solution in 1 ,3-butanediol. Among the acceptable parenterally acceptable diluents and solvents that may be employed are water, Ringer's solution, and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose, any bland fixed oil may be employed, including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid find use in the preparation of injectables. [00100] A sterile injectable oil-in-water nano or microemulsion can, for example, be prepared by 1) dissolving at least one compound of Formula (I) in an oily phase, such as, for example, a mixture of soybean oil and lecithin; 2) combining the Formula (I) containing oil phase with a water and glycerol mixture; and 3) processing the combination to form a microemulsion.
[00101] A sterile aqueous or oleaginous suspension can be prepared in accordance with methods already known in the art. For example, a sterile aqueous solution or suspension can be prepared with a non-toxic parenter ally- acceptable diluent or solvent, such as, for example, 1,3-butane diol; and a sterile oleaginous suspension can be prepared with a sterile non-toxic acceptable solvent or suspending medium, such as, for example, sterile fixed oils, e.g., synthetic mono- or diglycerides; and fatty acids, such as, for example, oleic acid.
[00102] Pharmaceutically acceptable carriers, adjuvants, and vehicles that may be used in the pharmaceutical compositions of this invention include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, self-emulsifying drug delivery systems (SEDDS) such as d- alpha-tocopherol polyethyleneglycol 1000 succinate, surfactants used in pharmaceutical dosage forms such as Tweens, polyethoxylated castor oil such as CREMOPFlOR® surfactant (BASF), or other similar polymeric delivery matrices, serum proteins, such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxypropylene -block polymers, polyethylene glycol and wool fat. Cyclodextrins such as alpha-, beta-, and gamma- cyclodextrin, or chemically modified derivatives such as hydroxyalkyl-cyclodextrins, including 2- and 3-hydroxypropyl-cyclodextrins, or other solubilized derivatives may also be advantageously used to enhance delivery of compounds of the formulae described herein.
[00103] The pharmaceutically active compounds of this invention can be processed in accordance with conventional methods of pharmacy to produce medicinal agents for administration to patients, including humans and other mammals. The pharmaceutical compositions may be subjected to conventional pharmaceutical operations such as sterilization and/or may contain conventional adjuvants, such as preservatives, stabilizers, wetting agents, emulsifiers, buffers etc. Tablets and pills can additionally be prepared with enteric coatings. Such compositions may also comprise adjuvants, such as wetting, sweetening, flavoring, and perfuming agents. [00104] The amounts of compounds that are administered and the dosage regimen for treating a disease condition with the compounds and/or compositions of this invention depends on a variety of factors, including the age, weight, gender, the medical condition of the subject, the type of disease, the severity of the disease, the route and frequency of administration, and the particular compound employed. Thus, the dosage regimen may vary widely, but can be determined routinely using standard methods. A daily dose of about 0.001 to 100 mg/kg body weight, preferably between about 0.005 and about 50 mg/kg body weight and most preferably between about 0.01 to 10 mg/kg body weight, may be appropriate. The daily dose can be administered in one to four doses per day.
[00105] In one embodiment, the compound is administered to the subject once a week. In another embodiment, the compound is administered to the subject once every two weeks.
[00106] For therapeutic purposes, the active compounds of this invention are ordinarily combined with one or more adjuvants appropriate to the indicated route of administration. If administered orally, the compounds may be admixed with lactose, sucrose, starch powder, cellulose esters of alkanoic acids, cellulose alkyl esters, talc, stearic acid, magnesium stearate, magnesium oxide, sodium and calcium salts of phosphoric and sulfuric acids, gelatin, acacia gum, sodium alginate, polyvinylpyrrolidone, and/or polyvinyl alcohol, and then tableted or encapsulated for convenient administration. Such capsules or tablets may contain a controlled-release formulation as may be provided in a dispersion of active compound in hydroxypropylmethyl cellulose.
[00107] Pharmaceutical compositions of this invention comprise at least one compound of Formula (I) and/or at least one salt thereof, and optionally an additional agent selected from any pharmaceutically acceptable carrier, adjuvant, and vehicle. Alternate compositions of this invention comprise a compound of the Formula (I) described herein, or a prodmg thereof, and a pharmaceutically acceptable carrier, adjuvant, or vehicle.
[00108] The compound in accordance with Formula (I) can be administered by any means suitable for the condition to be treated, which can depend on the need for site-specific treatment or quantity of Formula (I) compound to be delivered. The compounds and compositions of the present invention may, for example, be administered orally, mucosally, or parentally including intravascularly, intraperitoneally, subcutaneously, intramuscularly, and intrasternally. In another embodiment, the compounds and compositions of the present invention are administered intravenously.
Methods of Use
[00109] In one embodiment, the present invention provides the use of the described compounds or compositions for treating, suppressing or inhibiting a disease in a subject and the use of the described compounds or compositions for increasing the efficacy of an anti-CD20 therapy in a subject. In one embodiment, the anti-CD20 therapy comprises an anti-CD20 agent. In one embodiment, the anti- CD20 therapy comprises CAR-T therapy. In another embodiment, the anti-CD20 therapy comprises a bispecific antibody. In another embodiment, the anti-CD20 therapy comprises a T cell engager. In another embodiment, the anti-CD20 therapy comprises an antibody drug conjugate.
[00110] In another embodiment, the present invention provides a method of treating a disease comprising a NOTCH activating mutation in a subject comprising the step of administering to said subject a first composition comprising one or more compounds represented by the structure of Formula (I):
Figure imgf000035_0001
wherein:
Ri is— CH2CF3 or— CH2CH2CF3;
R2 is— CH2CF3,— CH2CH2CF3, or— CH2CH2CH2CF3;
R3 is H or— C¾;
each Ra is independently F, Cl,— CN,— OCH3, and/or— NHCH2CH2OCH3; and z is zero, 1, or 2
and a second composition comprising an anti-CD20 agent.
[00111] In one embodiment, the compound of Formula I comprises:
Figure imgf000035_0002
[00112] In another embodiment, the compound of Formula I comprises:
Figure imgf000036_0001
[00113] In another embodiment, the compound of Formula I comprises:
Figure imgf000036_0002
[00114] In one embodiment, the subject has activated Notch and low CD20. In one embodiment, the diseased cells in the subject comprise activated Notch and low CD20. In one embodiment, the disease in the subject is refractory to anti-CD20 treatment. In another embodiment, the subject has not previously been treated with anti-CD20, alone or in combination with other treatments.
[00115] In one embodiment, a method is provided for increasing the efficacy of an anti-CD20 agent or other anti-CD20 therapy, comprising administering to a subject a compound of Formula (I) and said anti-CD20 agent or other therapy. In another embodiment, a method is provided for increasing the efficacy of an anti-CD20 monoclonal antibody comprising administering to a subject a compound of Formula (I) and an anti-CD20 monoclonal antibody, which in one embodiment comprises rituximab. In another embodiment, a method is provided for increasing the efficacy of an anti-CD20 monoclonal antibody comprising administering to a subject a compound of Formula (I) and an anti- CD20 monoclonal antibody, which in one embodiment comprises Ofatumumab. In another embodiment, a method is provided for increasing the efficacy of an anti-CD20 monoclonal antibody comprising administering to a subject a compound of Formula (I) and an anti-CD20 monoclonal antibody, which in one embodiment comprises Obinutuzumab. In an embodiment, increasing the efficacy of the anti-CD20 monoclonal antibody comprises decreasing resistance to the anti-CD20 monoclonal antibody. In another embodiment, increasing the efficacy of the anti-CD20 monoclonal antibody comprises prolonging survival in the subject. In another embodiment, increasing the efficacy comprises achieving complete remission in the subject. In another embodiment, increasing the efficacy comprises achieving partial remission in the subject. In another embodiment, increasing the efficacy comprises achieving stable disease in the subject. In another embodiment, achieving stable disease in the subject comprises decreasing the level of Minimal Residual Disease (MRD) in the subject. In another embodiment, achieving stable disease in the subject comprises decreasing the progression of disease and/or rate of MRD. Any other measure of increasing efficacy, or combination of measures, known in the art is also within the scope of the invention as described herein.
[00116] In one embodiment, a method is provided for treating a disease comprising a NOTCH activating mutation, comprising administering to a subject a compound of Formula (I) and an anti- CD20 agent, which in one embodiment, comprises an anti-CD20 monoclonal antibody, which in one embodiment comprises rituximab, ofatumumab, obinutuzumab, or a combination thereof. In one embodiment, the NOTCH activating mutation is any NOTCH activating mutation. In one embodiment, the NOTCH activating mutation is a NOTCH1 activating mutation. In another embodiment, the NOTCH activating mutation is a NOTCH2 activating mutation. In another embodiment, the NOTCH activating mutation is a NOTCH3 activating mutation. In another embodiment, the NOTCH activating mutation is a NOTCH4 activating mutation. In one embodiment, benzodiazepinone compounds as described herein increase expression of CD20. In another embodiment, benzodiazepinone compounds as described herein are effective via a different mechanism of action.
[00117] In one embodiment, the disease comprises a lymphoid neoplasm. In another embodiment, the lymphoid neoplasm comprises a CD20 leukemia. In one embodiment, the lymphoid neoplasm comprises Chronic Lymphocytic Leukemia (CLL). In another embodiment, the lymphoid neoplasm comprises Small Lymphocytic Leukemia (SLL), mantle cell lymphoma (MCL), marginal zone lymphoma, diffuse large B-cell lymphoma (DLBCL), splenic diffuse red pulp small B-cell lymphoma, follicular lymphoma, or a combination thereof. In another embodiment, the lymphoid neoplasm comprises pediatric T-cell acute lymphoblastic leukemia/lymphoma (T-ALL), adult T- ALL, pediatric early T-cell precursor acute lymphoblastic leukemia (ETP-ALL), adult ETP-ALL, Adult T-cell leukemia/lymphoma, or a combination thereof. In another embodiment, the disease is associated with low CD20 expression levels in the subject. In one embodiment, the disease comprises Richter Syndrome. In another embodiment, the disease associated with low CD20 expression levels comprises Plasmablastic lymphoma, Primary effusion lymphoma, Large B-cell lymphoma arising from HHV8-associated multicentric Castleman’s disease, ALK+ large B cell lymphoma, or a combination thereof.
[00118] In one embodiment, a method is provided for treating CLL in a subject, comprising administering to a subject a compound of Formula (I) and an anti-CD20 therapy, which in one embodiment comprises an anti-CD20 agent. In one embodiment, the CLL is associated with low CD20 expression levels in the subject.
[00119] In another embodiment, a method is provided for treating a lymphoma in a subject, comprising administering to a subject a compound of Formula (I) and an anti-CD20 therapy. In one embodiment, the lymphoma is associated with low CD20 expression levels in the subject.
[00120] In another embodiment, a method is provided for treating a non-Flodgkin’s lymphoma in a subject, comprising administering to a subject a compound of Formula (I) and an anti-CD20 therapy. In one embodiment, the lymphoma is associated with low CD20 expression levels in the subject.
[00121] In another embodiment, a method is provided for treating a lymphoma in a subject, comprising administering to a subject a compound of Formula (I) and an anti-CD20 therapy. In one embodiment, the lymphoma is associated with low CD20 expression levels in the subject.
[00122] In another embodiment, a method is provided for treating a diffuse large B-cell lymphoma (DLBCL) in a subject, comprising administering to a subject a compound of Formula (I) and an anti- CD20 therapy. In one embodiment, the lymphoma is associated with low CD20 expression levels in the subject.
[00123] In another embodiment, a method is provided for treating a mantle cell lymphoma (MCL) in a subject, comprising administering to a subject a compound of Formula (I) and an anti-CD20 therapy. In one embodiment, the lymphoma is associated with low CD20 expression levels in the subject.
[00124] In one embodiment, the anti-CD20 therapy comprises an anti-CD20 agent, which in one embodiment, comprises an anti-CD20 monoclonal antibody, which in one embodiment comprises rituximab, ofatumumab, obinutuzumab, or a combination thereof.
[00125] In one embodiment, low CD20 expression levels are associated with one or more Notch 1 activating mutations. In another embodiment, low CD20 expression levels are associated with one or more Notch 2 activating mutations. In another embodiment, low CD20 expression levels are associated with one or more Notch 3 activating mutations. In another embodiment, low CD20 expression levels are associated with one or more Notch 4 activating mutations.
[00126] In one embodiment, the present invention provides the use of a therapeutically acceptable amount of one or more compounds or compositions as described herein for treating, suppressing or inhibiting a proliferative disease in a subject. In another embodiment, the present invention provides the use of a therapeutically effective amount of one or more compounds or compositions as described herein for treating, suppressing or inhibiting a proliferative disease in a subject. In another embodiment, the present invention provides the use of a synergistically effective amount of one or more compounds or compositions as described herein for treating, suppressing or inhibiting a proliferative disease in a subject. In another embodiment, the present invention provides the use of a synergistically therapeutically effective amount of one or more compounds or compositions as described herein for treating, suppressing or inhibiting a proliferative disease in a subject.
[00127] In one embodiment, the proliferative disease comprises a Desmoid tumor.
[00128] In one embodiment, the proliferative disease comprises a pre-cancerous condition or a benign proliferative disorder.
[00129] In one embodiment, the term "pre-cancerous" or, alternatively,“pre-malignant” as used herein interchangeably refers to diseases, syndromes or other conditions associated with an increased risk of cancer. Pre-cancer conditions in the context of the present invention include, but are not limited to: breast calcifications, vaginal intra-epithelial neoplasia, Barrett's esophagus, atrophic gastritis, dyskeratosis congenital, sideropenic dysphagia, lichen planus, oral submucous fibrosis, actinic keratosis, solar elastosis, cervical dysplasia, leukoplakia and erythroplakia.
[00130] In one embodiment, the term "benign hyperproliferative disorder" as used herein refers to a condition in which there is an abnormal growth and differentiation of cells and an increase in the amount of organic tissue that results from cell proliferation. The benign hyperproliferative disorder may be attributed to lack of response or inappropriate response to regulating factors, or alternatively to dysfunctional regulating factors. Non-limiting examples of benign hyperproliferative disorder are psoriasis and benign prostatic hyperplasia (BPH).
[00131] In another embodiment, the proliferative disease comprises a cancer.
[00132] In one embodiment, the cancer comprises a solid tumor. In another embodiment, the cancer comprises a hematological malignancy.
[00133] In one embodiment, a subject as described herein has cancer. In one embodiment, the term "cancer" in the context of the present invention includes all types of neoplasm whether in the form of solid or non-solid tumors and includes both malignant and premalignant conditions as well as their metastasis. In one embodiment, the cancer comprises a hematological malignancy.
[00134] In one embodiment, the cancer is a carcinoma, sarcoma, myeloma, leukemia, or lymphoma. In another embodiment, the cancer is a mixed type. [00135] In one embodiment, Mixed Type cancers contain several types of cells. The type components may be within one category or from different categories. Some examples are: adenosquamous carcinoma; mixed mesodermal tumor; carcinosarcoma; teratocarcinoma.
[00136] In another embodiment, the carcinoma comprises Adenoid Cystic Carcinoma (ACC). In another embodiment, the carcinoma comprises Gastro-esophageal junction carcinoma.
[00137] In one embodiment, the carcinoma is an adenocarcinoma. In another embodiment, the carcinoma is a squamous cell carcinoma.
[00138] In one embodiment, the sarcoma comprises osteosarcoma or osteogenic sarcoma (bone); Chondrosarcoma (cartilage); Leiomyosarcoma (smooth muscle); Rhabdomyosarcoma (skeletal muscle); Mesothelial sarcoma or mesothelioma (membranous lining of body cavities); Fibrosarcoma (fibrous tissue); Angiosarcoma or hemangioendothelioma (blood vessels); Liposarcoma (adipose tissue); Glioma or astrocytoma (neurogenic connective tissue found in the brain); Myxosarcoma (primitive embryonic connective tissue); and Mesenchymous or mixed mesodermal tumor (mixed connective tissue types).
[00139] In one embodiment, the cancer comprises myeloma, which, in one embodiment, is cancer that originates in the plasma cells of bone marrow. The plasma cells produce some of the proteins found in blood. In one embodiment, the cancer comprises multiple myeloma.
[00140] In another embodiment, the cancer comprises leukemia ("non-solid tumor" or "blood cancer"), which in one embodiment, is a cancer of the bone marrow (the site of blood cell production). In one embodiment, leukemia comprises myelogenous or granulocytic leukemia (malignancy of the myeloid and granulocytic white blood cell series); Lymphatic, lymphocytic, or lymphoblastic leukemia (malignancy of the lymphoid and lymphocytic blood cell series); and Polycythemia vera or erythremia (malignancy of various blood cell products, but with red cells predominating).
[00141] In another embodiment, the cancer comprises T-cell acute lymphoblastic leukemia (T- ALL). In another embodiment, the cancer comprises T-lymphoblastic leukemia/lymphoma (TLL). In another embodiment, the cancer comprises Chronic Lymphocytic Leukemia (CLL).
[00142] In another embodiment, the cancer comprises a lymphoma. In one embodiment, the lymphoma comprises an extranodal lymphoma. In one embodiment, the lymphoma comprises a Hodgkin lymphoma. In another embodiment, the lymphoma comprises a Non-Hodgkin lymphoma. In one embodiment, the lymphoma comprises a marginal zone B cell lymphoma, a diffuse large B cell lymphoma, or a mantle cell lymphoma. [00143] In another embodiment, the cancer is dependent upon Notch activation. In another embodiment, the cancer comprises a Notch-activating mutation. In another embodiment, the cancer is not dependent upon Notch activation.
[00144] In one embodiment, a cancer as described herein comprises a Notch activating genetic alteration. In another embodiment, a cancer as described herein comprises a Notch activating alteration. In another embodiment, a cancer as described herein comprises a Notch activating mutation. In another embodiment, a cancer as described herein comprises a Notch activating genetic mutation. In another embodiment, a cancer as described herein comprises a Notch mutation. In another embodiment, a cancer as described herein comprises a Notch altering mutation.
[00145] In one embodiment, Notch activating genetic alterations comprise a mutation in one or more Notch related genes. In one embodiment, the mutation in one or more Notch-related genes induces a gain of function (GOF) in Notch activity.
[00146] In another embodiment, the mutation in one or more Notch-related genes comprises a missense mutation. In another embodiment, the mutation in one or more Notch-related genes comprises a nonsense mutation. In another embodiment, the mutation in one or more Notch-related genes comprises an insertion mutation. In another embodiment, the mutation in one or more Notch- related genes comprises a deletion mutation. In another embodiment, the mutation in one or more Notch-related genes comprises a duplication mutation. In another embodiment, the mutation in one or more Notch-related genes comprises a frameshift mutation. In another embodiment, the mutation in one or more Notch-related genes comprises a repeat expansion. In another embodiment, the mutation in one or more Notch-related genes comprises a fusion.
[00147] In another embodiment, the cancer comprises astrocytoma, bladder cancer, breast cancer, cholangiocarcinoma (CCA), colon cancer, colorectal cancer, colorectal carcinoma, epithelial carcinoma, epithelial ovarian cancers, fibrosarcoma, gall bladder cancer, gastric cancer, glioblastoma, glioma, head and neck cancer, hepatocellular carcinoma, kidney cancer, liver cancer, lung cancer including non-small cell lung cancer (NSCLC), malignant fibrous histiocytoma (MFH), malignant pleural mesothelioma (MPM), medulloblastoma, melanoma, mesothelioma, neuroblastoma, osteosarcoma, ovarian adenocarcinoma, ovarian cancer, pancreatic adenocarcinoma, pancreatic cancer, prostate cancer, renal cell carcinoma (RCC), rhabdomyosarcoma, seminal vesicle cancer, and thyroid cancer. In one embodiment, the breast cancer is triple negative breast cancer.
[00148] As used herein, the term "cancer" includes the above categories of carcinoma, sarcoma, myeloma, leukemia, lymphoma and mixed type tumors. In particular, the term cancer includes: lymphoproliferative disorders, breast cancer, ovarian cancer, prostate cancer, cervical cancer, endometrial cancer, lung cancer, bone cancer, liver cancer, stomach cancer, bladder cancer, colon cancer, colorectal cancer, pancreatic cancer, cancer of the thyroid, head and neck cancer, cancer of the central nervous system, brain cancer, cancer of the peripheral nervous system, skin cancer, kidney cancer, as well as metastases of all the above. More particularly, as used herein the term may refer to: hepatocellular carcinoma, hematoma, hepatoblastoma, rhabdomyosarcoma, esophageal carcinoma, thyroid carcinoma, ganglioblastoma, glioblastoma, fibrosarcoma, myxosarcoma, liposarcoma, chondrosarcoma, osteogenic sarcoma, chordoma, angiosarcoma, endotheliosarcoma, Ewing's tumor, leimyosarcoma, rhabdotheliosarcoma, invasive ductal carcinoma, papillary adenocarcinoma, melanoma, squamous cell carcinoma, basal cell carcinoma, adenocarcinoma (well differentiated, moderately differentiated, poorly differentiated or undifferentiated), renal cell carcinoma, hypernephroma, hypernephroid adenocarcinoma, bile duct carcinoma, choriocarcinoma, seminoma, embryonal carcinoma, Wilms' tumor, testicular tumor, lung carcinoma including small cell, non- small and large cell lung carcinoma, bladder carcinoma, glioma, astrocyoma, medulloblastoma, craniopharyngioma, ependymoma, pinealoma, retinoblastoma, neuroblastoma, colon carcinoma, rectal carcinoma, hematopoietic malignancies including all types of leukemia and lymphoma including: acute myelogenous leukemia, acute myelocytic leukemia, acute lymphocytic leukemia, chronic myelogenous leukemia, chronic lymphocytic leukemia, mast cell leukemia, multiple myeloma, myeloid lymphoma, Hodgkin's lymphoma, non-Hodgkin's lymphoma, Waldenstrom’s Macroglobulinemia.
[00149] In another embodiment, the administration of the combined compositions as described herein reduces growth of the cells of a solid tumor or hematological malignancy by 40%, 50%, 60%, 70%, 80%, 90% or 95% compared to growth of the cells of the solid tumor or hematological malignancy that have not been treated with the combined compositions, i.e. have been treated with either one of the compositions, have been treated via a different cancer treatment, or have not been treated.
[00150] In another embodiment, the present invention provides methods of increasing or lengthening survival of a subject having a neoplasia. As used herein, the term“neoplasia” refers to a disease characterized by the pathological proliferation of a cell or tissue and its subsequent migration to or invasion of other tissues or organs. Neoplasia growth is typically uncontrolled and progressive, and occurs under conditions that would not elicit, or would cause cessation of, multiplication of normal cells. Neoplasias can affect a variety of cell types, tissues, or organs, including but not limited to an organ selected from the group consisting of bladder, colon, bone, brain, breast, cartilage, glia, esophagus, fallopian tube, gallbladder, heart, intestines, kidney, liver, lung, lymph node, nervous tissue, ovaries, pleura, pancreas, prostate, skeletal muscle, skin, spinal cord, spleen, stomach, testes, thymus, thyroid, trachea, urogenital tract, ureter, urethra, uterus, and vagina, or a tissue or cell type thereof. Neoplasias include cancers, such as sarcomas, carcinomas, or plasmacytomas (malignant tumor of the plasma cells).
[00151] In one embodiment, a subject as described herein is being treated with or has been previously treated with radiation therapy, chemotherapy, transplantation, immunotherapy, hormone therapy, or photodynamic therapy.
[00152] In one embodiment, a method is provided for treating cancer comprising administering to a mammal in need thereof a combination of a compound of Formula (I), an anti-CD20 agent, and optionally, one or more additional anti-cancer agents. In one embodiment, the additional anti-cancer agent comprises Chlorambucil, Fludarain, Pentostatin, Ciclophosphamide, F1DMP, Bendamustine, or a combination thereof. In one embodiment, the cancer comprises CLL.
[00153] In another embodiment, the additional anti-cancer agent comprises cisplatin, dasatinib, paclitaxel, tamoxifen, or a combination thereof.
[00154] In one embodiment, the“additional anti-cancer agent” refers to a drug selected from any one or more of the following: alkylating agents (including nitrogen mustards, alkyl sulfonates, nitrosoureas, ethylenimine derivatives, and triazenes); anti-angiogenics (including matrix metalloproteinase inhibitors); antimetabolites (including adenosine deaminase inhibitors, folic acid antagonists, purine analogues, and pyrimidine analogues); antibiotics or antibodies (including monoclonal antibodies, anthracyclines); aromatase inhibitors; cell-cycle response modifiers; enzymes; farnesyl-protein transferase inhibitors; hormonal and antihormonal agents and steroids (including synthetic analogs, glucocorticoids, estrogens/anti-estrogens [e.g., SERMs], androgens/anti-androgens, progestins, progesterone receptor agonists, and luteinizing hormone releasing [LF1RF1] agonists and antagonists); insulin-like growth factor (IGF)/insulin-like growth factor receptor (IGFR) system modulators (including IGFR1 inhibitors); integrin-signaling inhibitors; kinase inhibitors (including multi-kinase inhibitors and/or inhibitors of Src kinase or Src/abl, cyclin dependent kinase [CDK] inhibitors, panHer, Fler-1 and Fler-2 antibodies, VEGF inhibitors, including anti-VEGF antibodies, EGFR inhibitors, PARP (poly ADP-ribose polymerase) inhibitors, mitogen- activated protein [MAP] inhibitors, MET inhibitors, MEK inhibitors, Aurora kinase inhibitors, PDGF inhibitors, and other tyrosine kinase inhibitors or serine/threonine kinase inhibitors; microtubule- disruptor agents, such as ecteinascidins or their analogs and derivatives; microtubule-stabilizing agents such as taxanes, and the naturally-occurring epothilones and their synthetic and semi-synthetic analogs; microtubule-binding, destabilizing agents (including vinca alkaloids); topoisomerase inhibitors; prenyl-protein transferase inhibitors; platinum coordination complexes; signal transduction inhibitors; and other agents used as anti-cancer and cytotoxic agents such as biological response modifiers, growth factors, and immune modulators.
[00155] In one embodiment, a method is provided for treating cancer comprising administering to a mammal in need thereof a combination of a compound of Formula (I) and an additional anti-cancer agent, which is one embodiment, comprises an anti-CD20 agent; administering a glucocorticoid; and optionally, one or more additional anti-cancer agents. An example of a suitable glucocorticoid is dexamethasone.
[00156] In one embodiment, a method is provided for treating cancer comprising administering to a mammal in need thereof a combination of a compound of Formula (I) and an additional anti-cancer agent, which is one embodiment, comprises an anti-CD20 agent; administering carboplatin; and optionally, one or more additional anti-cancer agents.
[00157] Specific regimens of the methods of treating, suppressing or inhibiting a disease in a subject and the uses of the described compounds or compositions for increasing the efficacy of therapies as described herein can be varied as appropriate by one of skill in the art without departing from the scope of the invention. One of ordinary skill in the art would readily be able to determine a suitable treatment plan in accordance with the invention, based on the individual’ s needs. Factors to consider in determining such plans include, without limitation, the subject’s mutational status, age, and comorbidities, as well as various other factors readily recognized by the ordinarily skilled artisan. Definitions
[00158] Unless specifically stated otherwise herein, references made in the singular may also include the plural. For example,“a” and“an” may refer to either one, or one or more.
[00159] The definitions set forth herein take precedence over definitions set forth in any patent, patent application, and/or patent application publication incorporated herein by reference.
[00160] Listed below are definitions of various terms used to describe the present invention. These definitions apply to the terms as they are used throughout the specification (unless they are otherwise limited in specific instances) either individually or as part of a larger group.
[00161] As used herein, the term "administering" refers to bringing in contact with a compound of the present invention. In one embodiment, the compositions are applied locally. In another embodiment, the compositions are applied systemically. Administration can be accomplished to cells or tissue cultures, or to living organisms, for example humans.
[00162] As used herein, the terms "administering," "administer," or "administration" refer to delivering one or more compounds or compositions to a subject parenterally, enterally, or topically. Illustrative examples of parenteral administration include, but are not limited to, intravenous, intramuscular, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcuticular, intraarticulare, subcapsular, subarachnoid, intraspinal and intrasternal injection and infusion. Illustrative examples of enteral administration include, but are not limited to oral, inhalation, intranasal, sublingual, and rectal administration. Illustrative examples of topical administration include, but are not limited to, transdermal and vaginal administration. In particular embodiments, an agent or composition is administered parenterally, optionally by intravenous administration or oral administration to a subject.
[00163] In one embodiment, a composition of the present invention comprises a pharmaceutically acceptable composition. In one embodiment, the phrase“pharmaceutically acceptable” is employed herein to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
[00164] In one embodiment, a composition of the present invention is administered in a therapeutically effective amount. In one embodiment, a“therapeutically effective amount” is intended to include an amount of a compound of the present invention alone or an amount of the combination of compounds claimed or an amount of a compound of the present invention in combination with other active ingredients effective to act as an inhibitor to a NOTCH receptor, effective to inhibit gamma secretase, or effective to treat or prevent proliferative diseases such as cancer. In one embodiment, a "therapeutically effective amount" of a composition of the invention is that amount of composition which is sufficient to provide a beneficial effect to the subject to which the composition is administered.
[00165] As used herein,“treating” or“treatment” cover the treatment of a disease-state in a mammal, particularly in a human, and include: (a) preventing the disease-state from occurring in a mammal, in particular, when such mammal is predisposed to the disease-state but has not yet been diagnosed as having it; (b) inhibiting the disease-state, i.e., arresting its development; and/or (c) relieving the disease-state, i.e., causing regression of the disease state.
[00166] In one embodiment treating includes induction therapy. In another embodiment, treating includes treating patients who are not responsive or refractory to anti-CD20 therapy.
[00167] In one embodiment,“treating” refers to both therapeutic treatment and prophylactic or preventative measures, wherein the object is to prevent or lessen the targeted pathologic condition or disorder as described hereinabove. Thus, in one embodiment, treating may include directly affecting or curing, suppressing, inhibiting, preventing, reducing the severity of, delaying the onset of, reducing symptoms associated with the disease, disorder or condition, or a combination thereof Thus, in one embodiment,“treating” refers inter alia to delaying progression, expediting remission, inducing remission, augmenting remission, speeding recovery, increasing efficacy of or decreasing resistance to alternative therapeutics, or a combination thereof In one embodiment,“preventing” refers, inter alia, to delaying the onset of symptoms, preventing relapse to a disease, decreasing the number or frequency of relapse episodes, increasing latency between symptomatic episodes, or a combination thereof In one embodiment,“suppressing” or“inhibiting”, refers inter alia to reducing the severity of symptoms, reducing the severity of an acute episode, reducing the number of symptoms, reducing the incidence of disease-related symptoms, reducing the latency of symptoms, ameliorating symptoms, reducing secondary symptoms, reducing secondary infections, prolonging patient survival, or a combination thereof
[00168] In one embodiment, the term“decreasing the size of the tumor” as used herein is assessed using the“Response Evaluation Criteria In Solid Tumors” (RECIST). In one embodiment, RECIST measures reduction in tumor size by measuring the longest dimension of a target lesion. In one embodiment, the target lesion is selected on the basis of its size (lesion with the longest diameter) and its suitability for accurate repeated measurements (either by imaging techniques or clinically). In one embodiment, all other lesions (or sites of disease) are identified as non-target lesions and are also recorded at baseline. Measurements of these lesions are not required, but the presence or absence of each is noted throughout follow-up.
[00169] In one embodiment, the term“decreasing the volume of the tumor” as used herein is assessed using the radiological tumor response evaluation criteria. Whereby, the tumor is measured in two dimensions its maximum diameter (width) in the translation plane and its largest perpendicular diameter on same image (thickness), according to the World Health Organization (WHO).
[00170] According to any of the methods of the present invention and in one embodiment, a subject as described herein is human. In another embodiment, the subject is mammalian. In another embodiment, the subject is a primate, which in one embodiment, is a non-human primate. In another embodiment, the subject is murine, which in one embodiment is a mouse, and, in another embodiment is a rat. In another embodiment, the subject is canine, feline, bovine, equine, caprine, ovine, porcine, simian, ursine, vulpine, or lupine. In one embodiment, the subject is a chicken or fish.
[00171] In one embodiment, the compositions as described herein comprise the components of the composition (i.e., one or more anti-cancer agents and one or more gamma secretase inhibitors comprising a compound of Formula (I)) as described herein. In another embodiment, the compositions as described herein consist of the components of the composition (i.e., one or more anti cancer agents and one or more gamma secretase inhibitors comprising a compound of Formula (I)) as described herein. In another embodiment, the compositions as described herein consist essentially of the components of the composition (i.e., one or more anti-cancer agents and one or more gamma secretase inhibitors comprising a compound of Formula (I)) as described herein.
[00172] It is to be understood that the compositions and methods of the present invention comprising the elements or steps as described herein may, in another embodiment, consist of those elements or steps, or in another embodiment, consist essentially of those elements or steps. In some embodiments, the term“comprise” refers to the inclusion of the indicated active agents, such as the anti-cancer agents and the gamma secretase inhibitor, as well as inclusion of other active agents, and pharmaceutically or physiologically acceptable carriers, excipients, emollients, stabilizers, etc., as are known in the pharmaceutical industry. In some embodiments, the term“consisting essentially of’ refers to a composition, whose only active ingredients are the indicated active ingredients. Flowever, other compounds may be included which are for stabilizing, preserving, etc. the formulation, but are not involved directly in the therapeutic effect of the indicated active ingredients. In some embodiments, the term“consisting essentially of’ may refer to components which facilitate the release of the active ingredient. In some embodiments, the term“consisting” refers to a composition, which contains the active ingredients and a pharmaceutically acceptable carrier or excipient.
Timing and Site of Administration
[00173] In one embodiment, the administration of the anti-cancer agents occurs prior to, concurrent with, or following the administration of the compound of Formula (I).
[00174] In one embodiment, the administration of the anti-cancer agents occurs at the same site as the administration of the compound of Formula (I).
[00175] In one embodiment, the compound of Formula (I) is administered daily. In another embodiment, the compound of Formula (I) is administered 2 or 3 times per day. In another embodiment, the compound of Formula (I) is administered twice weekly. In another embodiment, the compound of Formula (I) is administered three, four, five, or six times per week. In another embodiment, the compound of Formula (I) is administered weekly. In another embodiment, the compound of Formula (I) is administered biweekly. In another embodiment, the compound of Formula (I) is administered once every three weeks. In another embodiment, the anti-CD20 agent is administered once every three weeks. In one embodiment, the anti-CD20 agent is administered until inhibition of disease progression is detected. [00176] In one embodiment, the compound of Formula (I) is admini tered several days before and after the administration of the anti-cancer agent. In one embodiment, the compound of Formula (I) is administered 1, 2, 3, 4, or 5 days prior to the administration of the anti-cancer agent. In one embodiment, the compound of Formula (I) is administered 1 , 2, 3, 4, or 5 days subsequent to the administration of the anti-cancer agent. In another embodiment, the compound of Formula (I) is administered one day before and up to 9 days following anti-cancer agent administration. In another embodiment, the compound of Formula (I) is administered one day before and on days 1, 8, and 9 following anti-cancer agent administration. In another embodiment, the compound of Formula (I) is administered one day before and 9 days following anti-cancer agent administration. In another embodiment, the compound of Formula (I) is administered one day before and daily for 9 days following anti-cancer agent administration. In another embodiment, the compound of Formula (I) is administered one day before and on day 9 following anti-cancer agent administration.
[00177] In some embodiments, one or more compositions of the present invention are administered at least once during a treatment cycle. In some embodiments, the compositions of the present invention are administered to the subject on the same days. In some embodiments, the compositions of the present invention are administered to the subject on the different days. In some embodiments, one or more compositions of the present invention are administered to the subject on the same days and on different days according to treatment schedules.
[00178] In particular embodiments, one or more compositions of the present invention are administered to the subject over one or more treatment cycles. A treatment cycle can be at least two, at least three, at least four, at least five, at least six, at least seven, at least 14, at least 21, at least 28, at least 48, or at least 96 days or more. In one embodiment, a treatment cycle is 28 days. In certain embodiments, the compositions are administered over the same treatment cycle or concurrently over different treatment cycles assigned for each composition. In various embodiments, the treatment cycle is determined by a health care professional based on conditions and needs of the subject.
[00179] In some embodiments, a composition is administered on at least one day, at least two days, at least three days, at least four days, at least five days, at least six days, at least seven days, at least eight days, at least nine days, at least ten days, at least eleven days, at least twelve days, at least 13 days, at least 14 days, at least 21 days, or all 28 days of a 28 day treatment cycle. In particular embodiments, a composition is administered to a subject once a day. In other particular embodiments, a composition is administered twice a day. In certain embodiments a composition is administered more than twice a day. [00180] In one embodiment, one or more of the compositions as described herein are administered once per day. In another embodiment, one or more of the compositions as described herein are administered twice per day. In another embodiment, one or more of the compositions as described herein are administered three times per day. In another embodiment, one or more of the compositions as described herein are administered four times per day. In another embodiment, one or more of the compositions as described herein are administered once every two days, once every three days, twice a week, once a week, once every 2 weeks, once every 3 weeks.
[00181] In one embodiment, one or more of the compositions as described herein are administered for 7 days to 28 days. In another embodiment, one or more of the compositions as described herein are administered for 7 days to 8 weeks. In another embodiment, one or more of the compositions as described herein are administered for 7 days to 50 days. In another embodiment, one or more of the compositions as described herein are administered for 7 days to six months. In another embodiment, one or more of the compositions as described herein are administered for 7 days to one and half years. In another embodiment, one or more of the compositions as described herein are administered for 14 days to 12 months. In another embodiment, one or more of the compositions as described herein are administered for 14 days to 3 years. In another embodiment, one or more of the compositions as described herein are administered for several years. In another embodiment, one or more of the compositions as described herein are administered for one month to six months.
[00182] In one embodiment, one or more of the compositions as described herein are administered for 7 days. In another embodiment, one or more of the compositions as described herein are administered for 14 days. In another embodiment, one or more of the compositions as described herein are administered for 21 days. In another embodiment, one or more of the compositions as described herein are administered for 28 days. In another embodiment, one or more of the compositions as described herein are administered for 50 days. In another embodiment, one or more of the compositions as described herein are administered for 56 days. In another embodiment, one or more of the compositions as described herein are administered for 84 days. In another embodiment, one or more of the compositions as described herein are administered for 90 days. In another embodiment, one or more of the compositions as described herein are administered for 120 days.
[00183] The number of times a composition is administered to a subject in need thereof depends on the discretion of a medical professional, the disorder, the severity of the disorder, and the subject's response to the formulation. In some embodiments, a composition disclosed herein is administered once to a subject in need thereof with a mild acute condition. In some embodiments, a composition disclosed herein is administered more than once to a subject in need thereof with a moderate or severe acute condition. In the case wherein the subject's condition does not improve, upon the doctor's discretion the composition may be administered chronically, that is, for an extended period of time, including throughout the duration of the subject's life in order to ameliorate or otherwise control or limit the symptoms of the subject's disease or condition.
[00184] In the case wherein the subject's status does improve, upon the doctor's discretion the composition may administered continuously; or, the dose of drug being administered may be temporarily reduced or temporarily suspended for a certain length of time (i.e., a "drug holiday"). The length of the drug holiday varies between 2 days and 1 year, including by way of example only, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 10 days, 12 days, 15 days, 20 days, 28 days, 35 days, 50 days, 70 days, 100 days, 120 days, 150 days, 180 days, 200 days, 250 days, 280 days, 300 days, 320 days, 350 days, and 365 days. The dose reduction during a drug holiday may be from 10%- 100%, including by way of example only 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, and 100%.
Kits
[00185] The present invention further comprises combinations of the compositions of the present invention and, optionally, one or more additional agents in kit form, e.g., where they are packaged together or placed in separate packages to be sold together as a kit, or where they are packaged to be formulated together.
[00186] In certain embodiments, the kit comprises a therapeutic or prophylactic composition containing an effective amount of an inhibitor of CD20 in unit dosage form and an effective amount of the compound of Formula (I), as described herein. In particular embodiments, the cells further express at least one co-stimulatory ligand. In certain embodiments, the kit comprises a sterile container which contains therapeutic or prophylactic agents; such containers can be boxes, ampules, bottles, vials, tubes, bags, pouches, blister-packs, or other suitable container forms known in the art. Such containers can be made of plastic, glass, laminated paper, metal foil, or other materials suitable for holding medicaments.
[00187] If desired, the composition(s) are provided together with instructions for administering the composition(s) to a subject having or at risk of developing a neoplasia (e.g., multiple myeloma). The instructions will generally include information about the use of the composition for the treatment or prevention of a neoplasia (e.g., multiple myeloma). In other embodiments, the instructions include at least one of the following: description of the therapeutic agent; dosage schedule and administration for treatment or prevention of a neoplasia (e.g., multiple myeloma) or symptoms thereof; precautions; warnings; indications; counter-indications; overdosage information; adverse reactions; animal pharmacology; clinical studies; and/or references. The instructions may be printed directly on the container (when present), or as a label applied to the container, or as a separate sheet, pamphlet, card, or folder supplied in or with the container.
[00188] While certain features of the invention have been illustrated and described herein, many modifications, substitutions, changes, and equivalents will now occur to those of ordinary skill in the art. It is, therefore, to be understood that the appended claims are intended to cover all such modifications and changes as fall within the true spirit of the invention.
[00189] All patents, patent applications, and scientific publications cited herein are hereby incorporated by reference in their entirety.
[00190] The following example is presented in order to more fully illustrate the preferred embodiments of the invention. It should in no way be construed, however, as limiting the broad scope of the invention.
EXAMPLES
Example 1
[00191] The effect of g-secretase inhibitors (GSIs) on levels of CD20 in lymphoma cell lines was examined (Figure 1). Cells from five different lymphoma cell lines (SP49 (mantle cell lymphoma (MCL) with Notch4 GOF); Toledo (Diffuse large B-cell lymphoma (DLBCL)); RC (Double Hit DLBCL - MYC, BCL2); SUDHL-4 (DLBCL); and SUDHL-6 (DLBCL)) were treated for 7 days with 0, lnM, lOnM, lOOnM, 500nM, lOOOnM, and lOOOOnM of the following GSIs: Compound 1 (Figure 1A) or Compound 22 (Figure IB). Cell surface CD20 levels were observed by flow cytometry (FACS analysis). Both Compound 1 and Compound 22 increased cell surface CD20 levels in SP-49 cells (Notch4 GOF; Figures 1A-1B). Compound 1 also increased cell surface CD20 levels in SUDHL-4 cells (Figure 1A).
[00192] In a separate experiment, cells from lymphoma cell lines SUDHL-4 (DLBCL); Rec-l (MCL); and SP49 (MCL) were seeded at lxlO4 cells/well in a total volume of 250pl into a 96-well plate. The cells were cultured in RPMI supplemented with 10% FCS.
[00193] Compound 1 or Compound 22 were added to the cell cultures at concentrations of 10, 1, 0.5, 0.1, 0.01, 0.OOImM. Following 7 days of incubation at 37°C, the cells were collected and stained with anti CD20 antibody and cell surface CD20 levels were immediately analyzed by flow cytometry (FACS analysis).
[00194] Treatment with Compound 1 induced a dose-dependent increase in CD20 levels in the three lymphoma cell lines tested (Figure 2A). In addition, in this experiment, treatment with Compound 22 induced a dose-dependent increase in CD20 levels in SUDHL-4 and Rec-l lymphoma cell lines (Figure 2B, n=l).
[00195] Taken together, the preliminary data presented here demonstrate that Compound 1 increases CD20 levels in lymphoma cell lines.
Example 2
[00196] The effect of g-secretase inhibitors (GSIs) on cell viability in lymphoma cells was examined (Figure 3). Cells from three different lymphoma cell lines (SUDHL-4 (DLBCL); Rec-l (MCL); and SP49 (MCL)) were treated for 7 days with various concentrations of GSIs Compound 1 (Figure 3A) and Compound 22 (Figure 3B). Viability was determined by FACS analysis (FSC/SSC). Example 3
[00197] A further study can be conducted to show the efficacy of treating patients with a disease comprising a NOTCH activating mutation, in accordance with methods described herein.
[00198] The study will involve treating patients with a B cell lymphoma or a B cell leukemia with identifed Notch mutations wherein the level of CD20 expression is decreased. The study will include 2 arms: in arm A, the patients with B cell Lymphoma or leukemia are treated wth the standard of care, RCHOP (Rituximab; cyclophosphamide; doxorubicin (hydroxydaunomycin); vincristine (Oncovin®); prednisolone).
[00199] In arm B, the patients are treated with RCHOP + compounds and compositions described herein.
[00200] The endpoints of the study will include observing rate of complete remission, partial remission and stable disease, time of progression, progression free survival and overall survival and rate of Minimal Residual Disease (MDR).

Claims

CLAIMS What is claimed is:
1. A composition comprising one or more compounds represented by the structure of Formula
(I):
Figure imgf000054_0001
and/or at least one salt thereof, wherein:
Ri is -CH2CF3 or -CH2CH2CF3;
R2 is -CH2CF3, -CH2CH2CF3, or -CH2CH2CH2CF3;
R3 is H, -CH3 or Rx;
R4 is Fl or Ry;
Rx
is: -CH20C(0)CH(CH3)NH2, - CH3)2)NHC(0)CH(NH2)CH(C
Figure imgf000054_0002
Figure imgf000054_0003
Ry is: -SCH2CH(NH2)C(0)0H, -SCH2CH(NH2)C(0)0H3,
or -SCH2CH(NH2)C(0)0C(CH3)3;
Ring A is phenyl or pyridinyl;
each Ra is independently F, Cl, -CN, -OCH3, C1-3 alkyl, -CH2OH, -CF3,
cyclopropyl, -OCH3, -O(cyclopropyl) and/or -NHCH2CH2OCH3;
each Rb is independently F, Cl, -CH3, -CH2OH, -CF3, cyclopropyl, and/or -OCH3; y is zero, 1 or 2; and
z is zero, 1 , or 2,
in combination with an anti-CD20 agent.
2. The composition of claim 1 , wherein the compound of Formula (I) is represented by the structure of Compound (1):
Figure imgf000055_0001
The composition of claim 1 , wherein the compound of Formula (I) is represented by the structure of Compound
Figure imgf000055_0002
4. The composition of claim 1 , wherein the compound of Formula (I) is represented by the structure of Compound (22):
Figure imgf000055_0003
5. The composition of any of claims 1-4, wherein said anti-CD20 agent comprises an antibody.
6. The composition of claim 5, wherein the antibody comprises a monoclonal antibody.
7. The composition of claim 6, wherein the monoclonal antibody comprises rituximab.
8. A method of increasing the efficacy of an anti-CD20 therapy in a subject, comprising the step of administering to said subject a first composition comprising one or more compounds represented by the structure of Formula (I):
Figure imgf000056_0001
and/or at least one salt thereof, wherein:
Ri is -CH2CF3 or -CH2CH2CF3;
R2 is -CH2CF3, -CH2CH2CF3, or -CH2CH2CH2CF3 ;
R3 is H, -CH3 or Rx;
R4 is Fl or Ry;
Rx
is: -CH20C(0)CH(CH3)NH2, - CH3)2)NHC(0)CH(NH2)CH(C
Figure imgf000056_0002
Figure imgf000056_0003
Ry is: -SCH2CH(NH2)C(0)0H, -SCH2CH(NH2)C(0)0H3,
or -SCH2CH(NH2)C(0)0C(CH3)3;
Ring A is phenyl or pyridinyl;
each Ra is independently F, Cl, -CN, -OCH3, C1-3 alkyl, -CF120F1, -CF3,
cyclopropyl, -OCF13, -O(cyclopropyl) and/or -NHCH2CH2OCH3;
each Rb is independently F, Cl, -CH3, -CF120F1, -CF3, cyclopropyl, and/or -OCH3; y is zero, 1 or 2; and
z is zero, 1 , or 2
wherein said administering increases the efficacy of said anti-CD20 therapy in the subject.
9. The method of claim 8, wherein the anti-CD20 therapy comprises an antibody.
10. The method of claim 9, wherein the antibody comprises a monoclonal antibody.
11. The method of claim 8, wherein the anti-CD20 therapy comprises CAR-T therapy.
12. The method of any of claims 8-11, wherein said first composition and/or said anti-CD20 therapy is intravenously administered to said subject.
13. The method of any of clai s 8-12, wherein said first composition and/or said anti-CD20 therapy is orally administered to said subject.
14. The method of any of claims 8-13, wherein said first composition and said anti-CD20 therapy are administered together.
15. The method of any of claims 8-13, wherein said first composition and said anti-CD20 therapy are administered at separate sites or at separate times.
16. The method of claim 15, wherein said first composition is administered prior to said anti-CD20 therapy.
17. The method of claim 15, wherein said first composition is administered subsequent to said anti-CD20 therapy.
18. The method of any one of claims 15-17, wherein said first composition comprising Formula (I) is administered prior to and then again subsequent to said anti-CD20 therapy.
19. The method of any of claims 8-18, wherein the increasing the efficacy of the anti-CD20 therapy comprises decreasing resistance to the anti-CD20 therapy.
20. The method of any of claims 8-19, wherein the increasing the efficacy of the anti-CD20 therapy comprises prolonging survival in the subject.
21. The method of any of claims 8-20, wherein said subject has a disease.
22. The method of claim 21 , wherein the disease comprises a NOTCF1 activating mutation.
23. The method of claim 22, wherein the NOTCF1 activating mutation comprises a NOTCF11 activating mutation.
24. The method of claim 22, wherein the NOTCF1 activating mutation comprises a NOTCF12 activating mutation.
25. A method of treating a disease comprising a NOTCF11 activating mutation in a subject, the method comprising the step of administering to said subject a first composition comprising one or more compounds represented by the structure of Formula (I):
Figure imgf000057_0001
and/or at least one salt thereof, wherein:
Ri is -CH2CF3 or -CH2CH2CF3;
R2 is -CH2CF3, -CH2CH2CF3, or -CH2CH2CH2CF3 ; R3 is H, -CH3 or Rx;
R4 is H or Ry;
Rx
is: -CH20C(0)CH(CH3)NH2, -CH20C(0)CH(NH2)CH(CH3)2, -CH20C(0)CH((CH(
Figure imgf000058_0001
Ry is: -SCH2CH(NH2)C(0)0H, -SCH2CH(NH2)C(0)0H3,
or -SCH2CH(NH2)C(0)0C(CH3)3;
Ring A is phenyl or pyridinyl;
each Ra is independently F, Cl, -CN, -OCH3, C1-3 alkyl, -CH2OH, -CF3,
cyclopropyl, -OCF13, -O(cyclopropyl) and/or -NFlCFhCFhOCFb;
each Rb is independently F, Cl, -CFL, -CFl2OF[, -CF3, cyclopropyl, and/or -OCFL; y is zero, 1 or 2; and
z is zero, 1 , or 2
and a second composition comprising an anti-CD20 monoclonal antibody.
26. The method of claim 25, wherein the anti-CD20 monoclonal antibody comprises rituximab.
27. The method of any one of claims 21-26, wherein the disease comprises a lymphoid neoplasm.
28. The method of claim 27, wherein the lymphoid neoplasm comprises Chronic Lymphocytic Leukemia (CLL).
29. The method of any one of claims 21-26, wherein the disease comprises a lymphoma.
30. A method of treating Chronic Lymphocytic Leukemia (CLL) or a lymphoma associated with low CD20 expression levels in a subject, the method comprising the step of administering to said subject a first composition comprising one or more compounds represented by the structure of Formula (I):
Figure imgf000058_0002
and/or at least one salt thereof, wherein:
Ri is -CH2CF3 or -CH2CH2CF3;
R2 is -CH2CF3, -CH2CH2CF3, or -CH2CH2CH2CF3 ;
R3 is H, -CH3 or Rx;
R4 is H or Ry;
Rx
is: -CH20C(0)CH(CH3)NH2, -CH20C(0)CH(NH2)CH(CH3)2, -CH20C(0)CH((CH(
Figure imgf000059_0001
Ry is: -SCH2CH(NH2)C(0)0H, -SCH2CH(NH2)C(0)0H3,
or -SCH2CH(NH2)C(0)0C(CH3)3;
Ring A is phenyl or pyridinyl;
each Ra is independently F, Cl, -CN, -OCH3, C1-3 alkyl, -CH2OH, -CF3,
cyclopropyl, -OCFb, -O(cyclopropyl) and/or -NFICFhCFhOCFb;
each Rb is independently F, Cl, -CFb, -CH2OH, -CF3, cyclopropyl, and/or -OCFb; y is zero, 1 or 2; and
z is zero, 1 , or 2
and a second composition comprising rituximab.
31. The method of any one of claims 29-30, wherein the lymphoma comprises a mantle cell lymphoma (MCL).
32. The method of claim 31, wherein the lymphoma comprises a diffuse large B-cell lymphoma (DLBCL).
33. The method of any one of claims 21-32, wherein the disease is associated with low CD20 expression levels in the subject.
34. The method of any of claims 25-33, wherein said first composition and/or said second composition is intravenously administered to said subject.
35. The method of any of claims 25-33, wherein said first composition and/or said second composition is orally administered to said subject.
36. The method of any of claims 25-35, wherein said first composition and said second composition are administered together.
37. The method of any of claims 25-35, wherein said first composition and said second composition are administered at separate sites or at separate times.
38. The method of claim 37, wherein said first composition is administered prior to said second composition.
39. The method of claim 37, wherein said first composition is administered subsequent to said second composition.
40. The method of any one of claims 37-39, wherein said first composition comprising Formula (I) is administered prior to and then again subsequent to the administration of said second composition.
41. The method of any of claims 45-55, wherein the administering increases the efficacy of the second composition.
42. The method of claim 56, wherein increasing the efficacy of the second composition comprises decreasing resistance to the second composition .
43. The method of claim 56, wherein increasing the efficacy of the second composition comprises prolonging survival in the subject.
44. The method of any of claims 8-43, wherein the compound of Formula (I) comprises:
Figure imgf000060_0001
45. The method of any of claims 8-43, wherein the compound of Formula (I) comprises:
Figure imgf000060_0002
46. The method of any of claims 8-43, wherein the compound of Formula (I) comprises:
Figure imgf000061_0001
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